No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Evidence for two different heat transduction mechanisms in nociceptive primary afferents innervating monkey skin
Abstract
1. Mechano- and heat-sensitive A fibre nociceptors (AMHs) and C fibre nociceptors (CMHs) in hairy skin (forty-six AMHs and twenty-one CMHs) and in glabrous skin (fifty-nine AMHs and ten CMHs) of anaesthetized monkeys were tested with a 30 s, 53 degrees C heat stimulus, delivered by a laser thermal stimulator (0.1 s rise time, 7.5 mm diameter). 2. Two types of heat response were observed in hairy skin AMHs. Type I AMHs had a peak discharge towards the end of the stimulus, response latencies to heat of up to several seconds, a median heat threshold greater than 53 degrees C, and a mean conduction velocity of 25 m s-1 (n = 33). Type II AMHs had a peak discharge within 1-3 s, a mean response latency of 120 ms, a median heat threshold of 46 degrees C, and a mean conduction velocity of 15 m s-1 (n = 13). Type I AMH fibres were sensitized to heat, whereas heat responses of type II AMHs were suppressed following the intense heat stimulus. 3. In glabrous skin, only type I AMHs were found. The absence of type II AMHs is consistent with the absence of first pain to heat in glabrous skin. 4. C fibre nociceptors in hairy skin had a peak discharge near stimulus onset, a mean response latency of 100 ms and a median heat threshold of 41 degrees C. Heat responses of CMHs in glabrous skin were not significantly different from those in hairy skin. 5. Only type II AMHs had response latencies that were short enough to explain first pain to heat. Heat thresholds of type II AMHs were significantly higher than those of CMHs. 6. These results suggest two different heat transduction mechanisms in nociceptive afferents. For one, heat energy is quickly transduced into action potentials, and the peak discharge is reached soon after stimulus onset. For the other, the transduction of heat is distinctly slower, and the peak discharge occurs near the end of the stimulus. Chemically mediated sensitization may be involved in the second transduction mechanism.
... Indeed, when tested on the forearm, VAS reduction during the OA paradigm was clearly observed during the first 5-10 s of T3 [15,[27][28][29][30][31], whilst at the hand thenar, we found a significant VAS reduction after active rTMS only at the end of the 20 s T3 time interval. The second aspect to be considered refers to possible differences in nociceptor innervation between the thenar eminence and the forearm [19,36]. In primates, the transmission of noxious mechanical and heat stimuli to the spinal cord is mediated by A-fibre mechano-heat (AMH) and C-fibre mechano-heat (CMH) skin nociceptors, which are responsible for first and second pain sensations, respectively [19,36,37]. ...
... The second aspect to be considered refers to possible differences in nociceptor innervation between the thenar eminence and the forearm [19,36]. In primates, the transmission of noxious mechanical and heat stimuli to the spinal cord is mediated by A-fibre mechano-heat (AMH) and C-fibre mechano-heat (CMH) skin nociceptors, which are responsible for first and second pain sensations, respectively [19,36,37]. Two populations of AMH nociceptor were described: type I (AMH-I) afferents, characterized by a high heat threshold (median 53 • C) with a slow, wind-up response to heat (in the order of seconds); and type II (AMH-II) afferents, characterized by a low heat threshold (median 46 • C) and a short latency (in the order of tens of milliseconds). ...
... Two populations of AMH nociceptor were described: type I (AMH-I) afferents, characterized by a high heat threshold (median 53 • C) with a slow, wind-up response to heat (in the order of seconds); and type II (AMH-II) afferents, characterized by a low heat threshold (median 46 • C) and a short latency (in the order of tens of milliseconds). Whereas AMH-I and AMH-II afferents are similarly represented in the hairy skin [37], experimental evidence suggests that AMH-II afferents may be absent in the glabrous skin of primates [36,38,39]. As the AMH-II nociceptors are thought to be primarily involved in the induction of inhibitory temporal sharpening mechanisms underlying OA, their absence could explain why OA is not easily detectable at the thenar eminence [19,35]. ...
Offset analgesia (OA), which is defined as a disproportionately large reduction in pain perception following a small decrease in a heat stimulus, quantifies temporal aspects of endogenous pain modulation. In this study on healthy subjects, we aimed to (i) determine the Heat Pain Threshold (HPT) and the response to constant and dynamic heat stimuli assessing sensitization, adaptation and OA phenomena at the thenar eminence; (ii) evaluate the effects of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) of the primary motor cortex (M1) on these measures. Twenty-four healthy subjects underwent quantitative sensory testing before and after active or sham 10 Hz rTMS (1200 stimuli) of the left M1, during separate sessions. We did not observe any rTMS-related changes in the HPT or visual analogue scale (VAS) values recorded during the constant trial. Of note, at baseline, we did not find OA at the thenar eminence. Only after active rTMS did we detect significantly reduced VAS values during dynamic heat stimuli, indicating a delayed and attenuated OA phenomenon. rTMS of the left M1 may activate remote brain areas that belong to the descending pain modulatory and reward systems involved in the OA phenomenon. Our findings provide insights into the mechanisms by which rTMS of M1 could exert its analgesic effects.
... The stimulation protocol is illustrated in Figure 1. Lower stimulation intensities (540, 600 mJ) were applied to FH and FD compared to FS (600, 660 mJ) because hairy skin (FH, FD) and glabrous skin (FS) are known to differ in their heat response properties (Taylor et al., 1993;Treede et al., 1995;Granovsky et al., 2005). Following previous protocols (Sandrini et al., 2005), reflex activity was recorded from the anterior tibialis muscle (TA) and soleus muscle (SO). ...
... These measurements were performed at the end of the experiment (see Figure 4 for an individual example). The calculated conduction velocity was well in line with knowledge on the conduction velocity of C-fibers and did not differ between the two study groups (SCI: mean 1.34 ± 0.46 m/sec; NDC: mean 1.08 ± 0.38 m/sec; p > 0.05) (Treede et al., 1995). The conduction velocity of TW1 ranged between 5.2 and 16.7 m/sec, which corresponds well with A-delta fiber activity. ...
... Although a direct method of A-fiber blocking was not performed in the present study, the conduction velocities could be estimated. The results thus obtained indicated that the responses in both time windows were also in wellaccordance with the engagement of A-delta-fibers and C-fibers, respectively (Willer et al., 1979;Treede et al., 1995;Mørch et al., 2007). Systematic studies on the selective contribution of C-fibers to nociceptive withdrawal reflexes are rare, essentially based on animal studies and challenging with respect to the appropriate stimulation protocol (Schomburg et al., 2000;Kimura et al., 2004;Kimura and Kontani, 2008;Hsieh et al., 2015). ...
Investigating nocifensive withdrawal reflexes as potential surrogate marker for the spinal excitation level may widen the understanding of maladaptive nociceptive processing after spinal cord injury (SCI). The aim of this prospective, explorative cross-sectional observational study was to investigate the response behavior of individuals with SCI to noxious radiant heat (laser) stimuli and to assess its relation to spasticity and neuropathic pain, two clinical consequences of spinal hyperexcitability/spinal disinhibition. Laser stimuli were applied at the sole and dorsum of the foot and below the fibula head. Corresponding reflexes were electromyography (EMG) recorded ipsilateral. Motor responses to laser stimuli were analyzed and related to clinical readouts (severity of injury/spasticity/pain), using established clinical assessment tools. Twenty-seven participants, 15 with SCI (age 18–63; 6.5 years post-injury; AIS-A through D) and 12 non-disabled controls, [non-disabled controls (NDC); age 19–63] were included. The percentage of individuals with SCI responding to stimuli (70–77%; p < 0.001), their response rates (16–21%; p < 0.05) and their reflex magnitude (p < 0.05) were significantly higher compared to NDC. SCI-related reflexes clustered in two time-windows, indicating involvement of both A-delta- and C-fibers. Spasticity was associated with facilitated reflexes in SCI (Kendall-tau-b p ≤ 0.05) and inversely associated with the occurrence/severity of neuropathic pain (Fisher’s exact p < 0.05; Eta-coefficient p < 0.05). However, neuropathic pain was not related to reflex behavior. Altogether, we found a bi-component motor hyperresponsiveness of SCI to noxious heat, which correlated with spasticity, but not neuropathic pain. Laser-evoked withdrawal reflexes may become a suitable outcome parameter to explore maladaptive spinal circuitries in SCI and to assess the effect of targeted treatment strategies. Registration: https://drks.de/search/de/trial/DRKS00006779.
... 2,23 It is assumed that nonglabrous skin is rich in C and high as well as low threshold Ad-mechano-heat nociceptors (AMH-I and AMH-II), whereas glabrous skin lacks AMH-II nociceptors. 3,25,30,31 The fact that OA seems to be suppressed if studied in glabrous skin indicates that peripheral components (AMH-II fibers) are crucial for shaping the magnitude of the OA effect. However, the exact physiological mechanisms of OA are not fully understood, even though publications on OA have increased enormously in the last decade. ...
... Although the exact contributions of the peripheral and central components to pain adaptation are still unclear, it has been shown on the basis of electrophysiological studies that pain adaptation is primarily modulated peripherally. 15,31 An influencing factor on OA seems to be the pain adaptation behavior within the constant trials, as again, the OA effect was determined from the difference between offset and constant trial. Although numerous analytical approaches have been described to determine the magnitude of OA, subtracting CT from OT is, however, a wellestablished method to avoid overestimation of the OA effect. ...
Introduction:
Offset analgesia describes the effect of a slightly reduced nociceptive stimulus, resulting in a disproportionate large reduction in the pain perception. This effect may be associated with descending pain inhibition, but parameters influencing this phenomenon are poorly understood.
Objectives:
In this study, 2 separate experiments were conducted to investigate both, the spatial aspects of offset analgesia and the influence of different rates of temperature rise.
Methods:
In both experiments, 29 healthy participants received individualized and heat-based offset analgesia paradigms applied to the forearm, with continuous assessment of pain intensity. In experiment 1, offset analgesia paradigms with 3 different rates of temperature rise were applied, whereas in experiment 2, offset analgesia paradigms with 2 different heat application areas were used.
Results:
The results of experiment 1 showed that different temperature rates had no effect on the offset analgesia response (P > 0.05). Experiment 2, however, showed the influence of the size of a stimulated area on offset analgesia (P = 0.009), which can be explained mainly by the influence of spatial summation of pain and habituation processes.
Conclusions:
The study showed a lack of influence of different temperature rates on offset analgesia; however, spatial aspects of offset analgesia could be identified. These are most likely based on spatial summation of pain and altered adaptation to pain.
... Additionally, we defined two times (early = 0-3 s of the stimulation block; late = 3-14 s of the stimulation block), orthogonalized the later regressors with regard to the first ones, and carried out session-level analyses with these nowsplit regressors. The time intervals have been chosen to overcome habituation processes of heat pain (Treede et al. 1995) and to illustrate time-dependent activations according to zu Eulenburg et al. (2013) and Pomares et al. (2013). ...
... The utilized heat pain temperatures were well above the pain thresholds based on standard data for men and women younger than 40 described by Rolke et al. (2006). The analysis of the first 3 s of heat stimulation, examined TNA thalamic nuclei atlas, A anterior, CL central-lateral/lateral-posterior/medial-pulvinar, MD medio-dorsal, P pulvinar, VA ventral-anterior, VLD ventral-latero-dorsal, VLV ventral-latero-ventral, OTCA oxford thalamic connectivity atlas, OC occipital cortex, PFC pre-frontal cortex, PPC posterior parietal cortex, PreMC pre-motor cortex, PriMC primary motor cortex, SC sensory cortex, TC temporal cortex a As two tests are performed for each stimulus type and time frame (two stimulation sides) the significance threshold according to Bonferroni is set to α = 0.025 to overcome habituation processes (Treede et al. 1995), also did not result in BOLD responses within the thalamus. The same protocol to elicit heat pain has been used in prior experiments of our study group and evoked reliable activations (e.g., of the insula, ACC, and S1) but not within the thalamus (Habig et al. 2017;Schirner et al. 2014). ...
Objectives
The thalamus plays an important role in the mediation and integration of various stimuli (e.g., somatosensory, pain, and vestibular). Whether a stimulus-specific and topographic organization of the thalamic nuclei exists is still unknown. The aim of our study was to define a functional, in vivo map of multimodal sensory processing within the human thalamus.
Methods
Twenty healthy individuals (10 women, 21–34 years old) participated. Defined sensory stimuli were applied to both hands (innocuous touch, mechanical pain, and heat pain) and the vestibular organ (galvanic stimulation) during 3 T functional MRI.
Results
Bilateral thalamic activations could be detected for touch, mechanical pain, and vestibular stimulation within the left medio-dorsal and right anterior thalamus. Heat pain did not lead to thalamic activation at all. Stimuli applied to the left body side resulted in stronger activation patterns. Comparing an early with a late stimulation interval, the mentioned activation patterns were far more pronounced within the early stimulation interval.
Conclusions
The right anterior and ventral-anterior nucleus and the left medio-dorsal nucleus appear to be important for the processing of multimodal sensory information. In addition, galvanic stimulation is processed more laterally compared to mechanical pain. The observed changes in activity within the thalamic nuclei depending on the stimulation interval suggest that the stimuli are processed in a thalamic network rather than a distinct nucleus. In particular, the vestibular network within the thalamus recruits bilateral nuclei, rendering the thalamus an important integrative structure for vestibular function.
... Almost all of these studies used stimulation with heated extracellular solution, which is at least one order of magnitude slower than the transduction process itself. Early human laser-evoked potentials (LEP) and monkey electrophysiology studies had already suggested a rapid transduction mechanism for noxious heat based on rapid laser heating [39]. Therefore, in the last years, infrared lasers with a high rate of temperature change were also used to apply heat stimuli to dorsal root ganglion neurons or transfected human embryonic kidney cells (HEK293, [11,16,28,44]). ...
... [40]) are co-expressed with TRPV1 in nociceptive neurons [14,21]. These may act in concert with TRPV1 to account for the transduction of more intense stimuli of longer duration [28]-as suggested by the two different heat transduction mechanisms found in nociceptive afferents [38,39]. ...
We studied the efficacy of a near-infrared laser (1475 nm) to activate rat dorsal root ganglion (DRG) neurons with short punctate radiant heat pulses (55 µm diameter) and investigated temporal and spatial summation properties for the transduction process for noxious heat at a subcellular level. Strength-duration curves (10–80 ms range) indicated a minimum power of 30.2mW for the induction of laser-induced calcium transients and a chronaxia of 13.9 ms. However, threshold energy increased with increasing stimulus duration suggesting substantial radial cooling of the laser spot. Increasing stimulus duration demonstrated suprathreshold intensity coding of calcium transients with less than linear gains (Stevens exponents 0.29/35mW, 0.38/60mW, 0.46/70mW). The competitive TRPV1 antagonist capsazepine blocked responses to short near-threshold stimuli and significantly reduced responses to longer duration suprathreshold heat. Heating 1/3 of the soma of a neuron was sufficient to induce calcium transients significantly above baseline ( p < 0.05), but maximum amplitude was only achieved by centering the laser over the entire neuron. Heat-induced calcium increase was highest in heated cell parts but rapidly reached unstimulated areas reminiscent of spreading depolarization and opening of voltage-gated calcium channels. Full intracellular equilibrium took about 3 s, consistent with a diffusion process. In summary, we investigated transduction mechanisms for noxious laser heat pulses in native sensory neurons at milliseconds temporal and subcellular spatial resolution and characterized strength duration properties, intensity coding, and spatial summation within single neurons. Thermal excitation of parts of a nociceptor spread via both membrane depolarization and intracellular calcium diffusion.
... For instance, it was shown that there was no OA effect in glabrous skin in contrast to non-glabrous skin 8,9 . Two explanations may clarify this phenomenon: First, it has been previously shown in animal models that the distribution of specific nociceptors differs between glabrous and non-glabrous skin [10][11][12] . Thus, one may argue that this may be due to the absence of specific A-delta fibers (low threshold A-delta mechanoheat nociceptors, AMH-II) in the palm, suggesting a role of peripheral input on the OA response 8 . ...
... While pain in the cheek and forearm adapt to the stimulus during the 30 seconds, pain in the mucosa and palm remains relatively constant. Although the underlyi ng mechanisms of pain adaptation are still unclear, electrophysiological studies have shown that pain adaptation is modulated primarily by specific peripheral fibers 11,46 . It has also been shown that stimulation temperatures above approximately 47 °C do not lead to adaptation independent of the perceived pain 47 , which could be a protective behavior of possible tissue damage. ...
Background:
Offset analgesia (OA) is commonly used to quantify endogenous pain inhibition. However, the potential role of afferent inputs and the subsequent peripheral factors from different body areas on the underlying mechanisms are still unclear.
Objectives:
The aim of this cross-sectional study was to compare the magnitude of OA in four different body areas representing a) glabrous and non-glabrous skin, b) trigeminal and extra-trigeminal areas, and c) intra- and extra-oral tissue.
Methods:
OA was assessed at the oral mucosa of the lower lip, at the skin of the cheek, the forearm and the palm of the hand in 32 healthy and pain-free participants. OA testing included two trials: (1) a constant trial (30 seconds of constant heat stimulation at an individualized temperature of Pain50 (pain intensity of 50 out of 100)), and (2) an offset trial (10 seconds of individualized Pain50 , followed by 5 seconds at Pain50 +1°C and 15 seconds at Pain50 ). Participants continuously rated their pain during each trial with a computerized visual analog scale.
Results:
A significant OA response was recorded at the oral mucosa (p<0.001, d=1.24), the cheek (p<0.001, d=0.84) and the forearm (p<0.001, d=1.04), but not at the palm (p=0.19, d=0.24). Significant differences were shown for OA recorded at the cheek versus the mucosa (p=0.02), and between palm and mucosa (p=0.007), but not between the remaining areas (p>0.05).
Conclusion:
This study suggests that intra-oral endogenous pain inhibition assessed with OA is enhanced and supports the role of peripheral mechanisms contributing to the OA response.
... The latency differences of 40 to 50 ms for N1, P1, and N2 is consistent with the activation or utilization time of thermonociceptors of approximately 40 ms. 31,[47][48][49] The distribution of latencies of heat responses of A fiber nociceptors in the hairy skin of monkeys was bimodal; for type II A fiber nociceptors, their threshold is around 438C, with conduction velocities between 9 and 15 m/second mediating fast pain. 47 Heat responsive type I A nociceptors conduction velocity was much faster (25 m/second). ...
... 31,[47][48][49] The distribution of latencies of heat responses of A fiber nociceptors in the hairy skin of monkeys was bimodal; for type II A fiber nociceptors, their threshold is around 438C, with conduction velocities between 9 and 15 m/second mediating fast pain. 47 Heat responsive type I A nociceptors conduction velocity was much faster (25 m/second). Data on human Ad fibers within that range is available. ...
Introduction
Demonstration of nociceptive fiber abnormality is important for diagnosing neuropathic pain and small fiber neuropathies. This is usually assessed by brief heat pulses using lasers, contact heat, or special electrodes. We hypothesized that pain-related evoked potentials to conventional surface electrical stimulation (PREPse) can index Aδ afferences despite tactile Aß fibers coactivation. PREPse may be more readily used clinically than contact heat evoked potentials (CHEPS).
Methods
Twenty-eight healthy subjects. Vertex (Cz-A1/A2) recordings. Electrical stimulation of middle finger and second toe with conventional ring, and forearm/leg skin with cup, electrodes. Contact heat stimulation to forearm and leg. Compression ischemic nerve blockade.
Results
PREPse peripheral velocities were within the midrange of Aδ fibers. N1-P1 amplitude increased with pain numerical rating scale graded (0–10) electrical stimulation ( n = 25) and decreased with increasing stimulation frequency. Amplitudes were unchanged by different presentation orders of four stimulation intensities. PREPse N1 (∼130 milliseconds) and N2 (∼345 milliseconds) peaks were approximately 40 milliseconds earlier than that with CHEPS. PREPse and CHEPS N1-N2 interpeak latency (∼207 milliseconds) were similar. PREPse became unrecordable with nerve blockade of Aδ fibers.
Conclusions
PREPse earlier N1 and N2 peaks, and similar interpeak N1-N2 latencies and central conduction velocities, or synaptic delays, to CHEPS are consistent with direct stimulation of Aδ fibers. The relation of vertex PREPse amplitude and pain, or the differential effects of frequency stimulation, is similar to pain-related evoked potential to laser, special electrodes, or contact heat stimulation. The relationship to Aδ was validated by conduction velocity and nerve block. Clinical utility of PREPse compared with CHEPS needs validation in somatosensory pathways lesions.
... Recently, it is reported that the ear and the surrounding areas also possess a low thermal threshold, indicating high sensitivity to the thermal variations [20]. Treede et al. found that the hairy skin is more heat sensitive than the glabrous part [36]. Recent research on the on-finger thermal feedback supported this finding of the difference on the thermal sensitivity between the hairy and the glabrous skins [41]. ...
... 1h3h, 1c3c, 5h7h, and 5c7c). This could be because of the high thermal sensitivity of the hairy skin in this area [36]. However, as the thickness of the hairy layer increases at the top location of the ThermEarhook prototype, the thermal stimuli were mostly blocked by the hair, resulting in the lower accuracy (averagely 35.4%) for the patterns involving the stimuli in this area (i.e., 1h2h, 2h3h, 2h4h, 1c2c, 2c3c, and 2c4c on the left; 5h6h, 6h7h, 6h8h, 5c6c, 6c7c, and 6c8c on the right). ...
Haptic feedbacks are widely adopted in mobile andwearable devices
to convey various types of notifications to the users. This paper investigates
the design and the evaluation of thermal haptic feedback
on an earable form factor with multiple thermoelectric (i.e. Peltier)
modules.We propose ThermEarhook, awearable device that can provide
hot and cold stimuli at multiple points on the auricular skin area.
To investigate users’ thermal perception on the auricular area, we
develop a series of ThermEarhook prototypes with 3, 4, and 5 Peltier
modules. While most existing research utilized the constant level of
haptic signal for different users, our pilot study with ThermEarhook
shows that the auricular thermohaptic threshold varies across the
feedback locations and the users. With the user-customized thermohaptic
signals around the ear, our first study with 12 participants
reports on the selection of the auricular configuration with four TEC
modules on each side, considering the users’ identification accuracy
(averagely 99.3%) and preference.We then conduct three follow-up
studies and a total of 36 participants to further evaluate users’ perception
of spatial thermal patterns with ThermEarhook, and finalize
a set of multi-points auricular thermal patterns that can be reliably
perceived by the users with the average accuracy of 85.3%. Lastly,
we discuss the user-proposed potential applications of the thermal
haptic feedback with ThermEarhook.
... LEPs are event-related brain potentials related to the activation of rapidly adapting heat-sensitive polymodal Afiber nociceptors (Type 2 A-fiber mechano-and heatsensitive fibers, Type2-AMH) [25]. Their magnitude is thus dependent on the activation of these nociceptive afferents, the transmission of nociceptive input within these afferents, and the further transmission and processing of that input within the spinothalamic system. ...
... Each recording will include 1 min of EEG recording with eyes opened, one 30-s period with eyes closed, followed by a second 1-min recording with eyes opened. A frequency analysis of the magnitude of ongoing EEG oscillations will be used to assess the amplitude of ongoing EEG oscillations within the delta (1-4 Hz), theta (4-7 Hz), alpha (8-12 Hz), beta (15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), and gamma (40-90 Hz) oscillations, eyes opened and eyes closed. The signal processing steps are described in the operational manual. ...
Background
IMI2-PainCare-BioPain-RCT3 is one of four similarly designed clinical studies aiming at profiling a set of functional biomarkers of drug effects on the nociceptive system that could serve to accelerate the future development of analgesics, by providing a quantitative understanding between drug exposure and effects of the drug on nociceptive signal processing in human volunteers. IMI2-PainCare-BioPain-RCT3 will focus on biomarkers derived from non-invasive electroencephalographic (EEG) measures of brain activity.
Methods
This is a multisite single-dose, double-blind, randomized, placebo-controlled, 4-period, 4-way crossover, pharmacodynamic (PD) and pharmacokinetic (PK) study in healthy subjects. Biomarkers derived from scalp EEG measurements (laser-evoked brain potentials [LEPs], pinprick-evoked brain potentials [PEPs], resting EEG) will be obtained before and three times after administration of three medications known to act on the nociceptive system (lacosamide, pregabalin, tapentadol) and placebo, given as a single oral dose in separate study periods. Medication effects will be assessed concurrently in a non-sensitized normal condition and a clinically relevant hyperalgesic condition (high-frequency electrical stimulation of the skin). Patient-reported outcomes will also be collected. A sequentially rejective multiple testing approach will be used with overall alpha error of the primary analysis split between LEP and PEP under tapentadol. Remaining treatment arm effects on LEP or PEP or effects on EEG are key secondary confirmatory analyses. Complex statistical analyses and PK-PD modeling are exploratory.
Discussion
LEPs and PEPs are brain responses related to the selective activation of thermonociceptors and mechanonociceptors. Their amplitudes are dependent on the responsiveness of these nociceptors and the state of the pathways relaying nociceptive input at the level of the spinal cord and brain. The magnitude of resting EEG oscillations is sensitive to changes in brain network function, and some modulations of oscillation magnitude can relate to perceived pain intensity, variations in vigilance, and attentional states. These oscillations can also be affected by analgesic drugs acting on the central nervous system. For these reasons, IMI2-PainCare-BioPain-RCT3 hypothesizes that EEG-derived measures can serve as biomarkers of target engagement of analgesic drugs for future Phase 1 clinical trials. Phase 2 and 3 clinical trials could also benefit from these tools for patient stratification.
Trial registration
This trial was registered 25/06/2019 in EudraCT ( 2019%2D%2D001204-37 ).
... According to the literature, the selected temperature is well above the thermal threshold of C warm fiber, which has been reported to be as little as 1 °C above normal skin temperature (Lamotte and Campbell 1978;Darian-Smith et al. 1979), with maximum activity around 40-41 °C (Hensel and Iggo 1971;Hallin et al. 1981). The selected temperature is, however, also similar to the thermal threshold of C fiber nociceptors (40-41 °C Churyukanov et al. 2012;Schmidt et al. 2002;Treede et al. 1995)). The reported intensities showed that approx. ...
... The higher (noxious) stimulation temperature was on average 48.6 °C, which is above the thermal threshold of both Aδ fiber nociceptors (thermal threshold 46-47 °C, Treede et al. 1995;Churyukanov et al. 2012)) as well as C fiber nociceptors, as mentioned above. This agrees with the reported intensities, where approximately 80% of the stimuli were perceived as painful. ...
The two-point discrimination threshold (2PDT) has been used to investigate the integration of sensory information, especially in relation to spatial acuity. The 2PDT has been investigated for both innocuous mechanical stimuli and noxious thermal stimuli; however, previous studies used different stimulation modalities to compare innocuous and noxious stimuli. This study investigated the 2PDT in 19 healthy participants, using both thermal (laser) and mechanical stimulation modalities. Within each modality, both innocuous and noxious intensities were applied. Concurrent point stimuli were applied to the right volar forearm, with separation distances of 0–120 mm, in steps of 10 mm. 0 mm corresponds to a single point. Following each stimulus, the participants indicated the number of perceived points (1 or 2) and the perceived intensity (NRS: 0: no perception, 3: pain threshold, 10: maximum pain). The order of stimulation modality, intensity and distance was randomized. The 2PDT for innocuous and noxious mechanical stimuli was 34.7 mm and 47.1 mm, respectively. For thermal stimuli, the 2PDT was 80.5 mm for innocuous stimuli and 66.9 mm for noxious stimuli. The average NRS for thermal stimuli was 1.6 for innocuous intensities and 4.0 for noxious intensities, while for mechanical stimuli, the average NRS was 0.9 for innocuous intensities and 3.6 for noxious intensities. This study showed that the 2PDT highly depends on both stimulation modality and intensity. Within each modality, noxious intensities modulates the 2PDT differently, i.e., noxious intensities lowers the 2PDT for thermal stimuli, but increases the 2PDT for mechanical stimuli.
... PP and TS are psychophysical pain responses of spinally mediated facilitatory mechanisms. They rely on two different types of afferent fibers that converge on dorsal horn cells of the spinal cord (Price, Hu, Dubner, & Gracely, 1977;Treede, Meyer, Raja, & Campbell, 1995). If descending inhibitory mechanisms play a role in music-induced analgesia, both PP and TS should be inhibited, as demonstrated with the spinal nociceptive withdrawal reflex (Roy et al., 2012). ...
... During the first 30 th seconds of the heat tests, maximum pain ratings were reduced by approximately 25% during the music session. PP is a first pain-related phenomenon that correlates to A-delta fibers activity (Tousignant-Laflamme et al., 2008;Treede et al., 1995), along with the spinal nociceptive withdrawal reflex (the RIII reflex; Dowman, 1991;Willer, Boureau, & Be-Fessard, 1978). A-delta fibers transmitted nociceptive information to central transmission neurons with a fast conduction velocity. ...
Passive music listening has shown its capacity to soothe pain in several clinical and experimental studies. This phenomenon—known as music-induced analgesia—could partly be explained by the modulation of pain signals in response to the stimulation of brain and brainstem centers. We hypothesized that music-induced analgesia may involve inhibitory descending pain systems. We assessed pain-related responses to endogenous pain control mechanisms known to depend on descending pain modulation: peak of first pain (PP), temporal summation (TS), and diffuse noxious inhibitory control (DNIC). Twenty-seven healthy participants (14 men, 13 women) were exposed to a conditioned pain modulation paradigm during a 20-minute relaxing music session and a silence condition. Pain was continually measured with a visual analogue scale. Pain ratings were significantly lower with music listening (p < .02). Repeated measures ANOVA indicated significant differences between conditions within PP and TS (p < .05) but not in DNIC. Those findings suggested that music listening could strengthen components of the inhibitory descending pain pathways operating at the dorsal spinal cord level.
... Mechanical stimuli may be expected to preferentially activate mechanosensitive nociceptors, heat stimuli to activate heat-sensitive nociceptors and cold stimuli to activate cold-sensitive afferents. Moreover, some nociceptors are predominantly sensitive to phasic stimuli whereas other nociceptors respond preferentially to long-lasting tonic stimuli (Meyer & Campbell, 1981;Treede et al., 1995). Thresholds may also vary (Churyukanov et al., 2012;Treede et al., 1995). ...
... Moreover, some nociceptors are predominantly sensitive to phasic stimuli whereas other nociceptors respond preferentially to long-lasting tonic stimuli (Meyer & Campbell, 1981;Treede et al., 1995). Thresholds may also vary (Churyukanov et al., 2012;Treede et al., 1995). As an example, intense short-lasting phasic heat stimuli such as those generated by a high power infrared laser pulse directed onto the skin have been shown to generate responses almost exclusively related to the activation of one specific type of heat-sensitive afferent, so-called A-fibre Type 2 nociceptors, with very little contribution of other types of heat-sensitive nociceptors such as Type 1 A-fibre nociceptors and C-fibre nociceptors (Bromm & Treede, 1987). ...
For decades, basic research on the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need. In this opinion paper bringing together pain researchers from very different disciplines, the opportunities and challenges of translational pain research are discussed. The many factors that may prevent the successful translation of bench observations into useful and effective clinical applications are reviewed, including interspecies differences, limited validity of currently available preclinical disease models of pain, and limitations of currently used methods to assess nociception and pain in non‐human and human models of pain. Many paths are explored to address these issues, including the backward translation of observations made in patients and human volunteers into new disease models that are more clinically relevant, improved generalization by taking into account age and sex differences, and the integration of psychobiology into translational pain research. Finally, it is argued that preclinical and clinical stages of developing new treatments for pain can be improved by better preclinical models of pathological pain conditions alongside revised methods to assess treatment‐induced effects on nociception in human and non‐human animals.
Significance:
For decades, basic research of the underlying mechanisms of nociception has held promise to translate into efficacious treatments for patients with pain. Despite great improvement in the understanding of pain physiology and pathophysiology, translation to novel, effective treatments for acute and chronic pain has however been limited, and they remain an unmet medical need.
... Consequently, a signal is conducted through C and Adelta bers to the central nervous system, permitting a real evaluation of thermal nociceptive pathways [6; 25]. Therefore, CHEPs can be regarded as a reliable electrophysiological method available to evaluate central processing of pain [33]. ...
Patients with Failed Back Surgery Syndrome (FBSS) may suffer neuropathic pain (NP) and central sensitization. Contact heat evoked potential (CHEP) is a reliable tool for evaluating pain pathways. CHEPs alteration in FBSS patients could identify pain pathway impairment and, therefore, contribute to a better understanding of the FBSS pathophysiology. Healthyparticipants and FBSS ones underwent CHEPs, being applied to the lumbar (L1) region, and recorded in Cz and Pz. We employed the neurological exam and DN4 (douleur neuropathique 4 questions) questionnaire to diagnose NP. FBSS patients demonstrated reduced amplitude and increased latencies in CHEPs at L1. CHEPs parameters were used to compare the lumbar region (L1) between both groups. Normal values and ROC curves were obtained. 36 normal individuals and 16 patients were enrolled in this study. Distinctive results were uncovered between both groups concerning N2-P2 amplitudes (p=0.025), N2 latencies (p= 0.008) and P2 latencies (0.005) at L1. The multivariate analyses showed a difference between the groups regarding the CHEPs parameters (p=0.003). Considering the normative values from the CHEPs data and values obtained as a cutoff in the ROC curves, such a method was able to diagnose spinothalamic impairment in 64 and 73% of the patients, respectively. Since the stimulus was applied at L1 and the patients suffered from pain at L4, L5, and, S1, these findings suggest that central sensitization occurs in FBSS. Therefore, CHEPs may be regarded as a valuable method to assess pain pathway impairment in patients with FBSS.
... First, the overall pain level across participants was relatively low based on the subjective pain ratings, with the vast majority of ratings indicating less than a moderate amount of pain, particularly in the mechanical modality. These may have been the result of the specific stimulus intensities chosen, or of using the finger as the body site of stimulation, since glabrous skin lacks type II a delta fibers 138 . Nevertheless, we observed strong placebo effects of the ratings, as well as substantial variability across participants that allowed us to test for individual differences. ...
Placebo analgesia is a replicable and well-studied phenomenon, yet it remains unclear to what degree it includes modulation of nociceptive processes. Some studies find effects consistent with nociceptive effects, but meta-analyses show that these effects are often small. We analyzed placebo analgesia in a large fMRI study (N = 392), including placebo effects on brain responses to noxious stimuli. Placebo treatment caused robust analgesia in both conditioned thermal and unconditioned mechanical pain. Placebo did not decrease fMRI activity in nociceptive pain regions, including the Neurologic Pain Signature (NPS) and pre-registered spinothalamic pathway regions, with strong support from Bayes Factor analyses. However, placebo treatment reduced activity in pre-registered analyses of a second neuromarker, the Stimulus Intensity Independent Pain Signature (SIIPS), and several associated a priori brain regions related to motivation and value, in both thermal and mechanical pain. Individual differences in behavioral analgesia were correlated with neural changes in both thermal and mechanical pain. Our results indicate that processes related to affective and cognitive aspects of pain primarily drive placebo analgesia.
... In the past, the effect of age on pain perception has been greatly debated; nonetheless, there is now some agreement [32] that only HTh, tested on a restricted skin area by a thermode, is increased in chronic pain patients. We suggest that the peripheral dysfunction may affect the hairy skin, particularly the quickly adapting type II A fibers, which are vulnerable to repetitive heat stimuli [33]. In our experiments, the stimulation of a wide peripheral area with reduced Aδ fiber innervation could result in a reduced central summation, contributing to the increased HTh. ...
Objective: Interoception is the sense of the physiological condition of the body; it results from the integration of somatic information, including pain, with visceral information. The aim of the study was to assess whether interoceptive sensibility and awareness modulate the perception of experimental pain in healthy participants and recurrent/chronic pain patients. Methods: To assess whether interoceptive sensibility and awareness modulate the effects of experimental noxious stimuli, pain-free subjects (N=52) and patients with recurrent (N= 47) and chronic pain (N= 42) underwent the following psychophysical tests: von Frey filaments (punctate mechanical threshold), pressure pain threshold, heat and cold pain threshold and tolerance, and diffuse noxious inhibitory control (DNIC). They also completed the Body Perception Questionnaire Short Form (BPQ-SF), which discriminates between sub- and supradiaphragmatic interoception, and the Multidimensional Assessment of Interoceptive Awareness I (MAIA I), which measures multiple dimensions of interoceptive sensibility/awareness. Results: After controlling for age and psychopharmacological treatment, a significant difference in heat pain tolerance among groups (F=3.16; p=.047; η2=.06) was found cancelled however by all BPQ dimensions and noticing of MAIA I. Conclusion: Different mechanism of experimental pain perception can be suggested in subjects with and without pain, based on the role of interoceptive sensibility.
... The techniques used in present and previous studies regarding visuo-nociceptive interactions mostly targeted activation of the quickly responding cutaneous thermo-nociceptors that preferentially respond to phasic stimulation. Slow-adapting thinly myelinated and unmyelinated fibers were also described to respond preferentially to more tonic stimulation profiles (Bromm and Treede 1984;Meyer and Campbell 1981;Schepers and Ringkamp 2010;Treede et al. 1995Treede et al. , 1998. It might be relevant to use other stimulation techniques and procedures that preferentially activate those receptors to investigate whether multisensory interactions with thermo-nociceptive stimuli applied distantly could be facilitated by the activity of nociceptors more sensitive to sustained stimulation. ...
To protect our body against physical threats, it is important to integrate the somatic and extra-somatic inputs generated by these stimuli. Temporal synchrony is an important parameter determining multisensory interaction, and the time taken by a given sensory input to reach the brain depends on the length and conduction velocity of the specific pathways through which it is transmitted. Nociceptive inputs are transmitted through very slow conducting unmyelinated C and thinly myelinated Aδ nociceptive fibers. It was previously shown that to perceive a visual stimulus and a thermo-nociceptive stimulus applied on the hand as coinciding in time, the nociceptive stimulus must precede the visual one by 76 ms for nociceptive inputs conveyed by Aδ fibers and 577 ms for inputs conveyed by C fibers. Since spatial proximity is also hypothesized to contribute to multisensory interaction, the present study investigated the effect of spatial congruence between visual and nociceptive stimuli. Participants judged the temporal order of visual and nociceptive stimuli, with the visual stimuli flashed either next to the stimulated hand or next to the opposite unstimulated hand, and with nociceptive stimuli evoking responses mediated by either Aδ or C fibers. The amount of time by which the nociceptive stimulus had to precede the visual stimulus for them to be perceived as appearing concomitantly was smaller when the visual stimulus occurred near the hand receiving the nociceptive stimulus as compared to when it occurred near the contralateral hand. This illustrates the challenge for the brain to process the synchrony between nociceptive and non-nociceptive stimuli to enable their efficient interaction to optimize defensive reaction against physical dangers.
... Temperature TRP channels constitute the central heat transducers expressed by nociceptors. TRPV1 and TRPV4 are activated by temperatures ranging from 42 to 52°C [83,84] (more details reviewed by Schepers and Ringkamp [85]). Although the TRPV1 channel is the prototypical heat sensory [83], a recent study indicated that TRPV1, TRPM3 and TRPA1 are necessary to detect acute noxious heat [86]. ...
... However, one explanation for the differences in influences on CT versus OT could be the difference in physiological processing. It is suggested that pain adaptation to a moderate, constant heat stimulus is primarily mediated by peripheral mechanisms [53][54][55]. In comparison, both peripheral and central mechanisms are known to shape OA [8]. ...
A frequently used paradigm to quantify endogenous pain modulation is offset analgesia, which is defined as a disproportionate large reduction in pain following a small decrease in a heat stimulus. The aim of this study was to determine whether suggestion influences the magnitude of offset analgesia in healthy participants. A total of 97 participants were randomized into three groups (hypoalgesic group, hyperalgesic group, control group). All participants received four heat stimuli (two constant trials and two offset trials) to the ventral, non-dominant forearm while they were asked to rate their perceived pain using a computerized visual analogue scale. In addition, electrodermal activity was measured during each heat stimulus. Participants in both intervention groups were given a visual and verbal suggestion about the expected pain response in an hypoalgesic and hyperalgesic manner. The control group received no suggestion. In all groups, significant offset analgesia was provoked, indicated by reduced pain ratings (p < 0.001) and enhanced electrodermal activity level (p < 0.01). A significant group difference in the magnitude of offset analgesia was found between the three groups (F[2,94] = 4.81, p < 0.05). Participants in the hyperalgesic group perceived significantly more pain than the hypoalgesic group (p = 0.031) and the control group (p < 0.05). However, the electrodermal activity data did not replicate this trend (p > 0.05). The results of this study indicate that suggestion can be effective to reduce but not increase endogenous pain modulation quantified by offset analgesia in healthy participants.
... This may be related to different peripheral nociceptive signaling pathways with differential sensitivity to thermal, mechanical or chemical stimulus modalities. In particular, heat and mechanical sensitivity of primate nociceptive afferents are inversely related (Treede et al., 1998;Treede et al., 1995), and mechanically sensitive nociceptors tend to have larger axons and lower electrical thresholds (Weidner et al., 1999). Thus, our findings are likely to be predictive for mechanical pain but less so for heat pain. ...
Many individuals with chronic musculoskeletal pain (CMP) show impairments in their pain-modulatory capacity. Although stress plays an important role in chronic pain, it is not known if stress-induced analgesia (SIA) is affected in patients with CMP. We investigated SIA in 22 patients with CMP and 18 pain-free participants. Pain thresholds, pain tolerance and suprathreshold pain ratings were examined before and after a cognitive stressor that typically induces pain reduction (SIA). Whereas the controls displayed a significant increase in pain threshold in response to the stressor, the patients with CMP showed no analgesia. In addition, increased pain intensity ratings after the stressor indicated hyperalgesia (SIH) in the patients with CMP compared to controls. An exploratory analysis showed no significant association of SIA or SIH with spatial pain extent. We did not observe significant changes in pain tolerance or pain unpleasantness ratings after the stressor in patients with CMP or controls. Our data suggest that altered stress-induced pain modulation is an important mechanism involved in CMP. Future studies need to clarify the psychobiological mechanisms of these stress-induced alterations in pain processing and determine the role of contributing factors such as early childhood trauma, catastrophizing, comorbidity with mental disorders and genetic predisposition.
... Aδ nociceptors in hairy skin can be subdivided into Type I (HTMRs) and Type II (LTMRs) nociceptors (Treede et al., 1998(Treede et al., , 1995. Type I Aδ nociceptors respond to mechanical and chemical stimuli, as well as maintained heat stimuli. ...
Spinal cord stimulation (SCS) and external low-frequency peripheral nerve stimulation (LFS) are palliative neurostimulation interventions for intractable neuropathic pain. However, understanding of the neural mechanisms underlying SCS and LFS is limited. Neurostimulation parameters such as waveform type and intensity modulate peripheral and central nociceptive pathways, which influence their therapeutic effects. The current thesis aimed to investigate the effects of varying intensities of burst and tonic SCS on resting cortical oscillations and somatosensory processing, and the temporal dynamics of LFS on somatosensory processing. Effects of SCS on oscillatory dynamics were assessed in patients using burst and tonic SCS for neuropathic leg pain. Spontaneous resting oscillations and event-related desynchronisation during brushing of a pain-free leg were examined at four SCS intensities. Temporal effects of LFS applied to the radial nerve were examined using source dipole modelling in healthy volunteers at varying intensities. Change in resting EEG and nociceptive processing were investigated after LFS. Results of four empirical studies pointed towards intensity-related changes in cortical activation during both SCS and LFS. Greater intensities of SCS and LFS were associated with decreased cortical excitability primarily in central and parietal scalp regions. Facilitatory effects of stimulation intensity were also identified in sensorimotor sources. Cortical activation changes during processing of somatosensory input were found between burst and tonic SCS. Intensity-related changes in cortical excitability during SCS and LFS may be partially explained by the Gate Control Theory and long-term depression, respectively. Coexistence of attenuated cortical excitability and sensorimotor facilitation suggests that these neurostimulation interventions do not have simple gating effects. Results support different underlying mechanisms between burst and tonic SCS which are engaged during somatosensory input. Findings have important clinical implications for the palliative treatment of neuropathic pain syndromes.
... In addition, the behavioral detection response (i.e., a stabbing pain caused by heat and cold) induced by harmful radiant skin heating appears to also be mediated by Aδ nociceptor activation [69]. The reaction of myelinated Aδ-fibers to noxious heat indicates a sense of pain at a threshold of 43 to 45 • C [70], whereas C-fiber nociceptors have a pain sensing threshold value of 41 • C on average [71]. TRPV1, also known as the capsaicin receptor, is known as the major molecular transducer of polymodal nociceptors that detect heat [72]. ...
Zingiber officinale Roscoe (ginger) has long been used as an herbal medicine to treat various diseases, and its main sub-components, [6]-gingerol and [6]-shogaol, were also reported to have anti-inflammatory, anti-oxidant, and anti-tumor effects. However, their effects on various types of pain and their underlying mechanisms of action have not been clearly analyzed and understood yet. Thus, in this review, by analyzing 16 studies that used Z. officinale, [6]-gingerol, and [6]-shogaol on mechanical, spontaneous and thermal pain, their effects and mechanisms of action have been analyzed. Pain was induced by either nerve injury or chemical injections in rodents. Nine studies analyzed the analgesic effect of Z. officinale, and four and three studies focused on [6]-gingerol and [6]-shogaol, respectively. Seven papers have demonstrated the underlying mechanism of action of their analgesic effects. Studies have focused on the spinal cord and one on the dorsal root ganglion (DRG) neurons. Involvement and change in the function of serotonergic receptors (5-HT1A, B, D, and 5A), transient receptor potential vanilloid 1 (TRPV1), N-methyl-D-aspartate (NMDA) receptors, phosphorylated extracellular signal-regulated kinase 1/2 (pERK1/2), histone deacetylase 1 (HDAC1), voltage-gated sodium channel 1.8 (Nav1.8), substance P (SP), and sciatic nerve’s morphology have been observed.
... Interestingly, in humans, heat perception thresholds are generally expressed as the temperature of the stimulation device, although thresholds for thermoreceptor activation have often been described at the receptor level 16 . However, the temperature of the stimulated skin region depends on several factors, including the initial temperature of the skin, the diffusion capacity between the skin and the stimulation surface, the ability of the skin to distribute heat throughout the tissue, and the depth at which the thermoreceptors are located 75 Calibration, or re-calibration can have an advantage over fixed intensities (Appendix 2) in studies with multiple observations (e.g., longitudinal), as significant intra-individual differences exist when pain is assessed over days or weeks 41 or even within minutes 37 . Similarly, the effect of interindividual factors that modulate pain perception is reduced in such an approach. ...
To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body composition, differences in energy absorption and previous experience. Individualization requires calibration, a procedure already irritating the pain system but allowing to match the pain level across individuals. It leads to a higher variability of the stimulus intensity, thereby influencing the encoding of “noxiousness” reaching the central nervous system. Results might be less influenced by statistical phenomena such as ceiling/floor effects and the approach does not seem to rise ethical concerns. On the other hand, applying a fixed (standardized) intensity reduces the problem of intensity encoding leading to a large between-subjects variability in pain responses. Fixed stimulation intensities do not require pre-exposure. It can be proposed that one method is not preferable over another, however the choice depends on the study aim and the desired level of external validity. This paper discusses considerations for choosing the best approach for experimental pain studies and provides recommendations for different study designs.
... Myelinated Aδ-fiber nociceptors and C-fiber polymodal nociceptors are involved in pain signal transmission from the peripheral nervous system to the central nervous system (Kunimoto 2012;Baron et al. 2013;Iyengar et al. 2017). Myelinated Aδ-fiber nociceptors and C-fiber polymodal nociceptors possess TRPV1 and TRPV2, whose thresholds of channel opening are 43°C and 52°C, respectively and operate as heat-sensitive nociceptors (Treede et al. 1995). However, it remains unclear whether orofacial heat pain sensation changes with aging, even though it has been established that aging alters the excitability of nociceptive neurons innervating the extremities (Chakour et al. 1996;Namer 2010;Taguchi et al. 2010). ...
Aging affects various sensory functions of the body. However, the effect on the oral mucosal nociception has remain unclear, so this elucidation is very important. Therefore, this study aimed to evaluate the effect of age-related changes in transient receptor potential vanilloid 1 (TRPV1) and TRPV2 expression in the trigeminal ganglion (TG) neurons on intraoral mucosal heat sensitivity in the senescence-accelerated mouse prone 8 (SAMP8) model. We used 23-week-old (aged) and 7-week-old (young) SAMP8 mice. Heat stimulation was applied to the palatal mucosa under light anesthesia; moreover, the heat head withdrawal threshold (HHWT) was measured. We counted the number of TRPV1-immunoreactive (IR) and TRPV2-IR TG neurons innervating the palatal mucosa. Additionally, we investigated changes in HHWT when TRPV1 or TRPV2 antagonists (SB366791 or Tranilast) were administered to the palatal mucosa. Aged SAMP8 mice showed a higher HHWT than young SAMP8 mice. Compared with the aged SAMP8 mice, young SAMP8 mice showed a larger number of TRPV1-IR small-diameter neurons and a smaller number of TRPV2-IR medium-sized neurons innervating the palatal mucosa. SB366791 administration increased the HHWT in young, but not aged SAMP8 mice. Contrastingly, Tranilast administration increased the HHWT in aged, but not young SAMP8 mice. These results suggest that the modulation of heat pain sensitivity in the oral mucosa due to aging is dependent on changes in the TRPV1 and TRPV2 expression patterns in the TG neurons innervating the palatal mucosa.
... Interestingly, in humans, heat perception thresholds are generally expressed as the temperature of the stimulation device, although thresholds for thermoreceptor activation have often been described at the receptor level [15]. However, the temperature of the stimulated skin region depends on several factors, including the initial temperature of the skin, the diffusion capacity between the skin and the stimulation surface, the ability of the skin to distribute heat throughout the tissue, and the depth at which the thermoreceptors are located [72]. ...
To calibrate or not to calibrate? This question is raised by almost everyone designing an experimental pain study with supra-threshold stimulation. The dilemma is whether to individualize stimulus intensity to the pain threshold / supra-threshold pain level of each participant or whether to provide the noxious stimulus at a fixed intensity so that everyone receives the identical input. Each approach has unique pros and cons which need to be considered to i) accurately design an experiment, ii) enhance statistical inference in the given data and, iii) reduce bias and the influence of confounding factors in the individual study e.g., body composition, differences in energy absorption and previous experience. Individualization requires calibration, a procedure already irritating the pain system but allowing to match the pain level across individuals. It leads to a higher variability of the stimulus intensity, thereby influencing the encoding of “noxiousness” reaching the central nervous system. Results might be less influenced by statistical phenomena such as ceiling/floor effects and the approach does not seem to rise ethical concerns. On the other hand, applying a fixed (standardized) intensity reduces the problem of intensity encoding leading to a large between-subjects variability in pain responses. Fixed stimulation intensities do not require pre-exposure. It can be proposed that one method is not preferable over another, however the choice depends on the study aim and the desired level of external validity. This paper discusses considerations for choosing the best approach for experimental pain studies and provides recommendations for different study designs.
... The 775 exogenous source of these distal drives is currently unknown and is likely different from the ventrobasal 776 lemniscal thalamic drive inducing the initial feedforward MN response. Not only does the LE response 777begin at a greater latency from stimulation onset (~170 ms), reflecting in part that it is transmitted through 778 slow Aδ fibers from the periphery to the spinal cord(Bromm and Treede, 1984;Treede et al., 1995Treede et al., , 1988, 779 but early LE supragranular drive likely hales from non-sensory-specific ventromedial thalamus (VM) 780(Borszcz, 2006; Desbois and Villanueva, 2001; Glenn et al., 1982; Monconduit et al., 2003, 1999) or from 781 the secondary somatosensory cortex (SII) (Baumgärtner et al., 2006; Iannetti et al., 2005; Ploner et al., 782 1999; Qiu et al., 2006; Treede et al., 2003; Vierck et al., 2013). As such, the source of this initial drive may 783 ...
Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically-relevant tools that have long been used to measure electromagnetic fields in somatosensory cortex evoked by non-painful and painful somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in primary somatosensory cortex (SI) linked to non-painful and painful sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful or painful somatosensation. We examined the neocortical circuit mechanisms contributing to MN and LE responses in SI using the Human Neocortical Neurosolver (HNN) neural modeling software tool. HNN was specifically designed for biophysically principled interpretation of the cell and circuit origin of M/EEG signals (Neymotin et al., 2020). Detailed analysis of the timing and orientation of peaks in source localized SI current dipole responses from MN and laser-evoked (LE) stimulation showed that these features were robust and conserved across prior studies. The first peak in the MN response at ∼20 ms corresponds to outward-directed deep-to-superficial electrical current flow through the cortical laminae, while the initial LE response occurs later at ∼170 ms and is oriented in the opposite direction. Historically, these peaks have both been labeled N20 and N1, despite their opposite current orientations. Simulating the cellular and circuit-level mechanisms accounting for these and later peaks with HNN’s detailed laminar neocortical column model revealed that the MN response can be simulated with a sequence of layer-specific exogenous excitatory feedforward and feedback synaptic drive. This sequence was similar to that previously reported for tactile evoked responses (Jones et al., 2007; Neymotin et al., 2020), with the novel discovery of an early excitatory feedback input to superficial layers at ∼30 ms post-stimulus that facilitated generation of the MN response’s first prominent inward-oriented deflection, known historically as the P30. Simulations of the LE response revealed that the initial ∼170 ms inward-deflection required a burst of repetitive gamma-frequency (∼40 Hz) excitatory supragranular feedback drives, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI, and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as chronic and neuropathic pain.
... A re-analysis of our previous OA studies [50,51,53] confirms this effect also for continuous TPCE: there is a strong correlation between the pain reduction in the offset trial and the adaptation to pain in the constant heat trial, without temperature change. Although the underlying mechanisms of adaptation to a sustained pain stimulus are not yet fully understood, again predominantly peripheral processes are hypothesized [16,57] as shown, for example, in certain A-delta nociceptors by electrophysiological studies [20,23,54,55]. However, both habituation and adaptation are strongly dependent on individual differences in pain perception with a strong tendency to ...
Offset analgesia is characterized by a disproportionately large reduction in pain following a small decrease in a heat stimulus and is based on the phenomenon of temporal pain contrast enhancement (TPCE). The aim of this study is to investigate whether this phenomenon can also be induced by repetitive stimulation, i.e., by stimuli that are clearly separated in time. With this aim, the repetitive TPCE paradigm was induced in healthy, pain-free subjects (n=33) at the volar non-dominant forearm using heat stimuli. This paradigm was performed applying three different interstimulus intervals (ISIs): 5, 15, and 25 seconds. All paradigms were contrasted with a control paradigm without temperature change. Participants continuously rated the perceived pain intensity. In addition, electrodermal activity was recorded as a surrogate measure of autonomic arousal. Temporal pain contrast enhancement was confirmed for both ISI 5 seconds (p < 0.001) and ISI 15 seconds (p = 0.005), but not for ISI 25 seconds (p = 0.07), however the magnitude of TPCE did not differ between ISIs (p = 0.11). Electrodermal activity was consistent previous pain ratings, but showing significantly higher autonomic activity being measured. Thus, the phenomenon of temporal contrast enhancement of pain can also be induced by repetitive stimulation. Both the involvement of the autonomic nervous system and the involvement of habituation processes are conceivable, which consequently points to both central and peripheral mechanisms of TPCE.
Summary
The temporal contrast enhancement of pain and electrodermal activity can be provoked by stimuli that are clearly separated in time.
... 8 They can be assessed using threshold and tolerance measurements and subjectively characterized by pain scores. 9 The temperature perception has two extremes, minimal heat threshold (MHT) and maximum temperature tolerance (MTT). Hence these quantitative objective variables of temperature perception provide potential information about small fiber function. ...
Introduction
A wide variety of diseases alter the perceptions of different sensations, often evaluated in a subjective manner. Assessment of temperature perception and tolerance is a useful screening tool to evaluate the Degenerative and neuropathic changes of an individual. Therefore the current study was intended to design and develop an inexpensive device to quantify the heat threshold and tolerance in healthy participants.
Materials and methods
The study was carried out in 30 apparent healthy participants for heat threshold, and tolerance was recorded on both hands' thenar and dorsal sites on two occasions. The minimum temperature when the subject was perceived is threshold and maximum until the subject withstood tolerance. The data was collected using the electronically controlled device for these two extremes. The entire study was carried out at a controlled room temperature precisely.
Results
The heat threshold was 39.84 ± 2.33 °C, and the tolerance was perceived at 46.84 ± 3.36 °C. There were no intraindividual differences (p > 0.05) in the heat threshold measured on two different periods as well as between the two hands (p > 0.05). As expected, there were significantly higher threshold values on the palm's thenar aspect than dorsum (p < 0.05). The tolerance was significantly higher in the thenar aspect than the dorsum of both hands. (p < 0.01, p-0.03). There were no significant inter-hand differences of both surfaces of the hand.
Conclusion
Our study showed that the results of threshold and tolerance using the indigenously built device were consistent and reproducible proves the robustness of the methodology. It is a cost-effective and user-friendly device that provides quantitative results of temperature extremes.
... Longer pulses allowed deeper penetration of heat into the skin (Marchandise et al., 2014). Both A-delta and C-nociceptors respond to laser heat stimuli (TREEDE et al., 1995;Wooten et al., 2014) with activation thresholds of about 47°C versus 40°C, respectively [determined by heat pulses of 50 ms duration with an initial 10 ms ramp (Churyukanov et al., 2012)]. Hence, our stimulus may have activated both nociceptor classes, but certainly included heat-sensitive C-fibres. ...
Background
Intradermal injection of 1 µg nerve growth factor (NGF) causes sustained nociceptor sensitization. Slowly depolarizing electrical current preferentially activates C‐nociceptors.
Methods
We explored the differential contribution of A‐delta and C‐nociceptors in NGF‐sensitized skin using slowly depolarizing transcutaneous electrical current stimuli, CO2 laser heat, mechanical impact, and A‐fibre compression block. In 14 healthy volunteers, pain rating was recorded on a numeric scale at days 1–14 after NGF treatment. Ratings during A‐fibre conduction block were investigated at days 3 and 7 post‐NGF.
Results
Pain ratings to electrical, CO2 heat and mechanical impact stimuli were enhanced (>30%, p < .0005, ANOVA) at NGF‐injection sites. Axon reflex erythema evoked by electrical stimulation was also larger at NGF‐injection sites (p < .02, ANOVA). Diminution of pain during continuous (1 min) sinusoidal current stimulation at 4 Hz was less pronounced after NGF (p < .05, ANOVA). Pain ratings to electrical sinusoidal and mechanical impact stimuli during A‐fibre conduction block were significantly elevated at the NGF sites compared to NaCl‐treated skin (p < .05, ANOVA).
Conclusions
NGF‐induced sensitization of human skin to electrical and mechanical stimuli is primarily driven by C‐nociceptors with little contribution from A‐delta fibres. Less‐pronounced accommodation during ongoing sinusoidal stimulation suggests that NGF could facilitate axonal spike generation and conduction in primary afferent nociceptors in humans. Further studies using this sinusoidal electrical stimulation profile to investigate patients with chronic inflammatory pain may allow localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.
Significance
The application of novel slowly depolarizing electrical stimuli demonstrated a predominant C‐nociceptor sensitization in NGF‐treated skin. Increased pain ratings, larger axon reflex erythema and less accommodation of C‐fibres to ongoing sinusoidal stimulation all indicated an enhanced nociceptor discharge after NGF. A‐fibre conduction block had little effect on electrical and mechanical hyperalgesia skin in NGF‐treated compared to NaCl‐treated skin. This electrical stimulus profile may be applicable for patients with chronic inflammatory pain, allowing localized assessment of skin C‐nociceptors and their putative excitability changes under pathologic conditions.
... The findings reported above also lend insight into the role of cognitive effort in the experience and regulation of pain. The temperatures administered in the present study were above the activation threshold for nociceptors found within the skin (Plaghki and Mouraux, 2003;Treede et al., 1995) and show that the higher temperatures elicited a strong, painful sensation (max. temperature used: 49˚C). ...
Cognitive effort is described as aversive, and people will generally avoid it when possible. This aversion to effort is believed to arise from a cost–benefit analysis of the actions available. The comparison of cognitive effort against other primary aversive experiences, however, remains relatively unexplored. Here, we offered participants choices between performing a cognitively demanding task or experiencing thermal pain. We found that cognitive effort can be traded off for physical pain and that people generally avoid exerting high levels of cognitive effort. We also used computational modelling to examine the aversive subjective value of effort and its effects on response behaviours. Applying this model to decision times revealed asymmetric effects of effort and pain, suggesting that cognitive effort may not share the same basic influences on avoidance behaviour as more primary aversive stimuli such as physical pain.
... In addition to an obvious advantage of rapid cold stimulations in the measurement of perceptual thresholds, very high stimulation ramps allow synchronous activation of small fibers and thus improve the signal-tonoise ratio for the recording of cold-evoked potentials (CEPs) [23]. As cold stimuli activate A-delta fiber thermo-receptors that are sensitive only or preferentially to cold, CEP might be a possible way to assess a different subclass of A-delta fibers as compared with AMH Type II A-delta fibers activated by means of laser-evoked potentials and painful contact heat-evoked potentials [24,25]. ...
Objective:
This study used high-speed cooling of the skin and exact control of stimulus duration to measure the cold detection threshold in healthy participants. The objective was to compare the method of limits, in which the temperature is slowly and gradually increased/decreased until the subject perceives the stimulation, and the method of levels, in which the subject must detect brief thermal stimulations close to the threshold of perception.
Methods:
Twenty healthy volunteers (nine women, 11 men) aged 20-30 years participated in the study. The method of limits and method of levels were performed in all subjects in a counterbalanced order. Four cold detection thresholds were measured with the method of levels, with a temperature ramp of 300°C/sec and stimulus durations of 50 ms, 100 ms, 300 ms, and 500 ms. Three thresholds were measured with the method of limits, with temperature ramps of 1°C/sec, 2°C/sec, and 4°C/sec.
Results:
On average, the cold detection thresholds were -0.47°C below skin temperature with the method of levels and -1.67°C the method of limits. Interindividual variability was significantly lower with the method of levels than with the method of limits.
Conclusions:
These results suggest that the method of levels is more accurate than the method of limits for measuring cold detection threshold. The improvement of cold detection threshold measurement may provide new perspectives to more precisely assess the function of A-delta fibers and the spino-thalamic pathway.
Nociceptive pain perception is a remarkable capability of organisms to be aware of environmental changes and avoid injury, which can be accomplished by specialized pain receptors known as nociceptors with 4 vital properties including threshold, no adaptation, relaxation, and sensitization. Bioinspired systems designed using artificial devices are investigated to imitate the efficacy and functionality of nociceptive transmission. Here, an artificial pain‐perceptual system (APPS) with a homogeneous material and heterogeneous integration is proposed to emulate the behavior of fast and slow pain in nociceptive transmission. Retention‐differentiated poly[2‐methoxy‐5‐(3,7‐dimethyoctyoxyl)‐1,4‐phenylenevinylene] (MDMO‐PPV) memristors with film thicknesses of 160 and 80 nm are manufactured and adopted as A‐δ and C nerve fibers of nociceptor conduits, respectively. Additionally, a nociceptor mimic, the ruthenium nanoparticles (Ru‐NPs)‐doped MDMO‐PPV piezoresistive pressure sensor, is fabricated with a noxiously stimulated threshold of 150 kPa. Under the application of pricking and dull noxious stimuli, the current flows predominantly through the memristor to mimic the behavior of fast and slow pain, respectively, in nociceptive transmission with postsynaptic potentiation properties, which is analogous to biological pain perception. The proposed APPS can provide potential advancements in establishing the nervous system, thus enabling the successful development of next‐generation neurorobotics, neuroprosthetics, and precision medicine.
How pain spreads across body locations is a subject of debate. In this psychophysical experiment, we hypothesized that more intense noxious stimuli would lead to spread of pain, but more intense light stimuli would not produce perceptual radiation. Fifty healthy volunteers participated in this study wherein four intensities of noxious stimuli (43, 45, 47 and 49°C) were applied to glabrous (hand) and hairy skin (forearm) skin with 5s and 10s durations. Also, four different intensities of visual stimuli displayed on the target bodily area were utilized as a control. Participants provided pain (and light) spatial extent ratings as well as pain (and light) intensity ratings. In the extent rating procedure, participants adjusted the extent of the square displayed on the screen with the extent of pain (or light) which they experienced. Results showed that pain extent ratings showed statistically significant radiation of pain indicated by 13.42× greater spatial spread of pain (pain extent) than the area of the stimulation with 49°C (p < 0.001), in contrast to visual ratings which closely approximated the size of the stimulus (1.22×). Pain radiation was more pronounced in hairy than glabrous skin (p < 0.05) and was more pronounced with longer stimulus duration (p < 0.001). Pain intensity explained, on average, only 14% of the pain radiation variability. The relative independence of the pain radiation from perceived pain intensity indicates that distinct components of population coding mechanisms may be involved in the spatial representation of pain versus intensity coding.
Magneto- and/or electro-encephalography (M/EEG) are non-invasive clinically relevant tools that have long been used to measure electromagnetic fields in the somatosensory cortex evoked by innocuous and noxious somatosensory stimuli. Two commonly applied stimulation paradigms that produce distinct responses in the primary somatosensory cortex (SI) linked to innocuous and noxious sensations are electrical median nerve (MN) stimulation and cutaneous laser-evoked (LE) stimulation to the dorsum of the hand, respectively. Despite their prevalence, the physiological mechanisms that produce stereotypic macroscale MN and LE responses have yet to be fully articulated, limiting their utility in understanding brain dynamics associated with non-painful and/or painful somatosensation. Through a literature review, we detailed features of MN and LE responses source-localized to SI that are robust and reproducible across studies. We showed that the first peak in the MN response at ~20 ms post-stimulus (i.e., MN N1) corresponds to upward-directed deep-to-superficial electrical current flow through the cortical laminae, which is followed by downward-directed current at ~30 ms (i.e., MN P1). In contrast, the initial LE response occurs later at ~170 ms (i.e., LE N1) and is directed downward and opposite the direction of the MN N1. We then examined the neocortical circuit mechanisms contributing to the robust features of each response using the Human Neocortical Neurosolver (HNN) neural modeling software tool (Neymotin et al., 2020). Using HNN as a hypothesis development and testing tool, model results predicted the MN response can be simulated with a sequence of layer-specific thalamocortical and cortico-cortical synaptic drive similar to that previously reported for tactile evoked responses (S. R. Jones et al., 2007; Neymotin et al., 2020), with the novel discovery that an early excitatory input to supragranular layers at ~30 ms is an essential mechanism contributing to the downward current flow of the MN P1. Model results further predicted that the initial ~170 ms downward current flow of the LE N1 was generated by a burst of repetitive gamma-frequency (~40 Hz) excitatory synaptic drive to supragranular layers, consistent with prior reports of LE gamma-frequency activity. These results make novel and detailed multiscale predictions about the dynamic laminar circuit mechanisms underlying temporal and spectral features of MN and LE responses in SI and can guide further investigations in follow-up studies. Ultimately, these findings may help with the development of targeted therapeutics for pathological somatosensation, such as somatic sensitivity and acute neuropathic pain.
Offset analgesia (OA) is observed when pain relief is disproportional to the reduction of noxious input and is based on temporal contrast enhancement (TCE). This phenomenon is believed to reflect the function of the inhibitory pain modulatory system. However, the mechanisms contributing to this phenomenon remain poorly understood, with previous research focusing primarily on painful stimuli and not generalizing to non-painful stimuli. Therefore, the aim of this study was to investigate whether TCE can be induced by noxious as well as innocuous heat and cold stimuli. Asymptomatic subjects (n=50) were recruited to participate in two consecutive experiments. In a first pilot study (n=17), the parameters of noxious and innocuous heat and cold stimuli were investigated in order to implement them in the main study. In the second (main) experiment, subjects (n=33) participated in TCE paradigms consisting of four different modalities, including noxious heat, innocuous heat, noxious cold, and innocuous cold. The intensity of the sensations of each thermal modality was assessed using an electronic visual analog scale. Temporal contrast enhancement was confirmed for noxious heat (p < 0.001), noxious cold (p = 0.034) and innocuous cold (p = 0.002). Conversely, TCE could not be shown for innocuous heat (p = 1.00). No significant correlation between TCE modalities was found (r < 0.3, p > 0.05). The results suggest that TCE can be induced by both painful and non-painful thermal stimulation, but not by innocuous warm temperature. The exact underlying mechanisms need to be clarified. However, among other potential mechanisms, this may be explained by a thermo-specific activation of C-fiber afferents by innocuous heat and of A-fiber afferents by innocuous cold, suggesting involvement of A-fibers rather than C-fibers in TCE. More research is needed to confirm a peripheral influence.
Perspective
This psychophysical study presents the observation of temporal contrast enhancement during noxious heat, noxious cold, and innocuous cold stimuli, but not during stimulation with innocuous warm temperature in healthy volunteers. A better understanding of endogenous pain modulation mechanisms might be helpful in explaining the underlying aspects of pain disorders.
Variability in pain sensitivity arises not only from the differences in peripheral sensory receptors, but also from the differences in central nervous system pain inhibition and facilitation mechanisms. Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation but is susceptible to confounding when elicited with the skin-contact thermode, which adds the responses of touch-related Aβ low-threshold mechanoreceptors (LTMR) to nociceptive receptors. In the present study, we evaluate an alternative method involving with the use contactless cutaneous laser for TSP assessment. We show that repetitive laser stimulations, 1-second inter-stimulus interval, evoked reliable TSP responses in a significant proportion of healthy subjects (N = 36). Female (N = 18) reported greater TSP responses than male subjects confirming earlier studies of sex differences in central nociceptive excitability. Furthermore, repetitive laser stimulations during TSP induction induced increased time-frequency EEG responses. The present study demonstrates that repetitive laser stimulation may be an alternative to skin-contact methods for TSP assessment in patients and healthy controls. PERSPECTIVE: Temporal summation of pain (TSP) is an experimental protocol commonly used in human studies of pain facilitation. We show that the contactless cutaneous laser stimulation is a reliable alternative to the skin contact approaches for evoking more pain-related neural responses during TSP assessment.
Background:
Infrared laser stimulation is a valuable tool in pain research, its primary application being the recording of laser-evoked brain potentials (LEPs). Different types of laser stimulators, varying in their skin penetrance, are likely to have a large influence on the LEPs, when stimulating different skin types. The aim of this study was to investigate how LEPs depend on laser type and skin location.
Methods:
Two different laser stimulators (CO2 and Nd:YAP) were used to compare LEPs in healthy subjects. Stimuli were delivered to the hand dorsum and palm to investigate the effects of skin type on the evoked responses. Stimulus-evoked brain responses were recorded using EEG and perceived intensity ratings were recorded. Computational modelling was used to investigate the observed differences.
Results:
LEPs evoked by stimulation of the hairy skin were similar between CO2 and Nd:YAP stimulation. In contrast, LEPs elicited from the palm were markedly different and barely present for CO2 stimulation. There was a significant interaction between laser type and skin type (RM-ANOVA, p < 0.05) likely due to smaller CO2 LEPs in the palm. CO2 stimuli to the palm also elicited significantly lower perceived intensities. The computational model showed that the observed differences were explainable by the laser absorption characteristics and skin thickness affecting the temperature profile at the dermo-epidermal junction (DEJ).
Conclusions:
This study shows that LEP elicitation depends on the combination of laser penetrance and skin type. Low penetrance stimuli, from a CO2 laser, elicited significantly lower LEPs and perceived intensities in the palm.
Significance:
This study showed that the elicitation of laser-evoked potentials in healthy humans greatly depends on the combination of laser stimulator type and skin type. It was shown that high penetrance laser stimuli are capable of eliciting responses in both hairy and glabrous skin, whereas low penetrance stimuli barely elicited responses from the glabrous skin. Computational modelling was used to demonstrate that the results could be fully explained by the combination of laser type and skin thickness.
Numerous studies have used electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) to demonstrate that pain caused by noxious stimulation elicits a widespread array of brain responses. However, their functional significance remains heavily debated. A number of studies have attempted to simultaneously record EEG and fMRI responses to noxious stimuli, with the aim of combining the high temporal resolution of EEG with the high spatial resolution of fMRI, and thus define these responses more precisely. However, because EEG and fMRI do not sample necessarily the same neural activity, interpretation of these studies requires caution. This chapter (1) examines the general and practical issues related to the simultaneous collection of EEG and fMRI responses to noxious stimulation, (2) reviews the studies that have attempted to combine such recordings, and (3) illustrates how analysis of EEG data at the level of single-trials can be used to drive the analysis of simultaneously collected fMRI data, and how this EEG-informed blood oxygen level-dependent modelling approach can provide novel physiological information.
Objective
To compare nociceptive event-related brain potentials elicited by a high-speed contact-thermode vs. an infrared CO2 laser stimulator.
Methods
Contact heat-evoked potentials (CHEPs) and CO2 laser-evoked potentials (LEPs) were recorded in healthy volunteers using a high-speed contact-thermode (>200°C/s) and a temperature-controlled CO2 laser. In separate experiments, stimuli were matched in terms of target surface temperature (55°C) and intensity of perception. A finite-element model of skin heat transfer was used to explain observed differences.
Results
For 55°C stimuli, CHEPs were reduced in amplitude and delayed in latency as compared to LEPs. For perceptually matched stimuli (CHEPs: 62°C; LEPs: 55°C), amplitudes were similar, but CHEPs latencies remained delayed. These differences could be explained by skin thermal inertia producing differences in the heating profile of contact vs radiant heat at the dermo-epidermal junction.
Conclusions
Provided that steep heating ramps are used, and that target temperature is matched at the dermo–epidermal junction, contact and radiant laser heat stimulation elicit responses of similar magnitude. CHEPs are delayed compared to LEPs.
Significance
CHEPs could be used as an alternative to LEPs for the diagnosis of neuropathic pain. Dedicated normative values must be used to account for differences in skin thermal transfer.
Background:
Quantitative sensory testing (QST) assesses the functional integrity of small and large nerve fibre afferents and central somatosensory pathways; QST was assumed to provide insight into the mechanisms of neuropathy. We analysed QST profiles and phenotypes in diabetes mellitus patients to study whether these could differentiate patients with and without pain and neuropathy.
Methods:
A standardised QST protocol was performed and 'loss and gain of function' abnormalities were analysed in four groups of subjects: diabetic patients with painful (pDSPN; n=220) and non-painful distal symmetric polyneuropathy (nDSPN; n=219), diabetic patients without neuropathy (DM; n=23), and healthy non-diabetic subjects (n=37). Based on the QST findings, diabetic subjects were further stratified into four predefined prototypic phenotypes: sensory loss (SL), thermal hyperalgesia (TH), mechanical hyperalgesia (MH), and healthy individuals.
Results:
Patients in the pDSPN group showed the greatest hyposensitivity ('loss of function'), and DM patients showed the lowest, with statistically significant increases in thermal, thermal pain, mechanical, and mechanical pain sensory thresholds. Accordingly, the frequency of the SL phenotype was significantly higher in the pDSPN subgroup (41.8%), than expected (p<0.0042). The proportion of 'gain of function' abnormalities was low in both pDSPN and nDSPN patients without significant differences.
Conclusions:
There is a continuum in the sensory profiles of diabetic patients, with a more pronounced sensory loss in pDSPN group probably reflecting somatosensory nerve fibre degeneration. An analysis of 'gain of function' abnormalities (allodynia, hyperalgesia) did not offer a key to understanding the pathophysiology of spontaneous diabetic peripheral neuropathic pain.
A frequently used paradigm to quantify endogenous pain modulation is offset analgesia, which is defined as a disproportionate large reduction in pain following a small decrease in a heat stimulus. The aim of this study was to determine whether suggestion influences the magnitude of offset analgesia in healthy participants. A total of 102 participants were randomized into three groups (hypoalgesic group, hyperalgesic group, control group). All participants received four heat stimuli (two constant trials and two offset trials) to the ventral, non-dominant forearm while they were asked to rate their perceived pain using a computerized visual analogue scale. In addition, electrodermal activity was measured during each heat stimulus. Participants in both intervention groups were given a visual and verbal suggestion about the expected pain response in an hypoalgesic and hyperalgesic manner. The control group received no suggestion. In all groups, significant offset analgesia was provoked, indicated by reduced pain ratings (p < 0.001) and enhanced electrodermal activity level (p < 0.01). A significant group difference in the magnitude of offset analgesia was found between the three groups (F[2,94] = 4.81, p < 0.05). Participants in the hyperalgesic group perceived significantly more pain than the hypoalgesic group (p = 0.031) and the control group (p < 0.05). However, the electrodermal activity data did not replicate this trend (p > 0.05). The results of this study indicate that suggestion can be effective to reduce but not increase endogenous pain modulation quantified by offset analgesia in healthy participants.
Background
Adaptation to a constant sensory stimulus involves many sites along the path of sensory volleys towards perception. The evaluation of such phenomenon may be of clinical interest. We studied adaptation to a constant temperature stimulus in healthy subjects to set normative data and in patients with sensory polyneuropathy (SPN), as proof of concept.
Methods
Twenty‐six healthy subjects and 26 patients with SPN in the context of chemotherapy treatment with oxaliplatin for colon cancer were instructed to express through an electronic VAS system (eVAS); the level of sensation felt when a thermode set at either 39º, 41º, 43º, 45º or 47º was applied to their ventral forearm.
Results
The eVAS recordings showed typically an abrupt onset that slowed to approach maximum sensation and continued with a slow decrease indicating adaptation. The time to respond (TR), the velocity of the initial response (VR), the maximum sensation (MA), the time to reach MA (MAt), the onset of adaptation (AO) and the decrease in the sensation level with respect to MA at 30 s after stimulus application (SL30), were dependent on the temperature level in all subjects. However, patients showed significantly delayed TR, slowed VR, decreased MA, delayed AO and reduced SL30, with respect to healthy subjects. Differences were more pronounced at low‐temperature levels, with absent AO in 25 patients versus 2 healthy subjects at temperatures of 39º and 41ºC.
Conclusion
The study of adaptation to a constant temperature stimulus can furnish valuable data for the assessment of patients with SPN.
Significance
We studied perceptual changes in the intensity of thermoalgesic sensation during 30 s of constant temperature stimulation after an abrupt initial contact in healthy subjects and patients with sensory polyneuropathy. Patients showed delayed time to respond, decreased maximal sensation and reduced adaptation with respect to healthy subjects. Differences were more pronounced at low and intermediate temperatures (39ºC to 43ºC). The method is of easy implementation and shows clinically relevant abnormalities in patients with sensory polyneuropathy.
TRP channels play a central role in the transduction of thermal and nociceptive stimuli by free nerve endings. Most of the research on these channels has been conducted in vitro or in vivo in nonhuman animals and translation of these results to humans must account for potential experimental biases and interspecific differences. This study aimed at evaluating the involvement of TRPM8, TRPA1 and TRPV1 channels in the transduction of heat and cold stimuli by the human thermonociceptive system. For this purpose, we evaluated the effects of topical agonists of these 3 channels (menthol, cinnamaldehyde and capsaicin) on the event-related brain potentials (ERPs) elicited by phasic thermal stimuli (target temperatures: 10°C, 42°C, and 60°C) selected to activate cold Aδ thermoreceptors, warm sensitive C thermoreceptors and heat sensitive Aδ polymodal nociceptors. Sixty-four participants were recruited, 16 allocated to each agonist solution group (20% menthol, 10% cinnamaldehyde, .025% capsaicin and 1% capsaicin). Participants were treated sequentially with the active solution on one forearm and vehicle only on the other forearm for 20 minutes. Menthol decreased the amplitude and increased the latency of cold and heat ERPs. Cinnamic aldehyde decreased the amplitude and increased the latency of heat but not cold ERPs. Capsaicin decreased the amplitude and increased the latency of heat ERPs and decreased the amplitude of the N2P2 complex of the cold ERPs without affecting the earlier N1 wave or the latencies of the peaks. These findings are compatible with previous evidence indicating that TRPM8 is involved in innocuous cold transduction and that TRPV1 and TRPA1 are involved in noxious heat transduction in humans.
Perspective
By chemically modulating TRPM8, TRPA1 and TRPV1 reactivity (key molecules in the transduction of temperature) and assessing how this affected EEG responses to the activation of cold thermoreceptors and heat nociceptors, we aimed at confirming the role of these channels in a functional healthy human model.
Objective
We aimed to establish an objective neurophysiological test protocol that can be used to assess the somatosensory nervous system.
Methods
In order to assess most fiber subtypes of the somatosensory nervous system, repetitive stimuli of seven different modalities (touch, vibration, pinprick, cold, contact heat, laser, and warmth) were synchronized with the electroencephalogram (EEG) and applied on the cheek and dorsum of the hand and dorsum of the foot in 21 healthy subjects and three polyneuropathy (PNP) patients. Latencies and amplitudes of the modalities were assessed and compared. Patients received quantitative sensory testing (QST) as reference.
Results
We found reproducible evoked potentials recordings for touch, vibration, pinprick, contact-heat, and laser stimuli. The recording of warm-evoked potentials was challenging in young healthy subjects and not applicable in patients. Latencies were shortest within Aβ-fiber-mediated signals and longest within C-fibers. The test protocol detected function loss within the Aβ-fiber and Aδ-fiber-range in PNP patients. This function loss corresponded with QST findings.
Conclusion
In this pilot study, we developed a neurophysiological test protocol that can specifically assess most of the somatosensory modalities. Despite technical challenges, initial patient data appear promising regarding a possible future clinical application.
Significance
Established and custom-made stimulators were combined to assess different fiber subtypes of the somatosensory nervous system using modality-specific evoked potentials.
Objectives
In clinical neurophysiology practice, various methods of stimulation can be used to activate small-diameter nociceptive cutaneous afferents located in the epidermis. These methods include different types of laser and intraepidermal electrical stimulation techniques. The diffusion of the stimulation in the skin, inside or under the epidermis, depends on laser wavelength and electrode design, in particular. The aim of this study was to compare several of these techniques in their ability to selectively stimulate small nerve fibers.
Methods
In 8 healthy subjects, laser stimulation (using a CO2 or Nd:YAP laser) and intraepidermal electrical stimulation (using a micropatterned, concentric planar, or concentric needle electrode), were applied at increasing energy or intensity on the dorsal or volar aspect of the right hand or foot. The subjects were asked to define the perceived sensation (warm, pinprick, or electric shock sensation, corresponding to the activation of C fibers, Aδ fibers, or Aβ fibers, respectively) after each stimulation. Depending on the difference in the sensations perceived between dorsal (hairy skin with thin stratum corneum) and volar (glabrous skin with thick stratum corneum) stimulations, the diffusion of the stimulation inside or under the epidermis and the nature of the activated afferents were determined.
Results
Regarding laser stimulation, the perceived sensations turned from warm to pinprick with increasing energies of stimulation, in particular with the Nd:YAP laser, of which pulse could penetrate deep in the skin according to its short wavelength. In contrast, CO2 laser stimulation produced only warm sensations and no pricking sensation when applied to the glabrous skin, perhaps due to a thicker stratum corneum and the shallow penetration of the CO2 laser pulse. Regarding intraepidermal electrical stimulation using concentric electrodes, the perceived sensations turned from pinprick to a combination of pinprick and electrical shocks with increasing intensities. Using the concentric planar electrode, the sensations perceived at high stimulation intensity even consisted of electric shocks without concomitant pinprick. In contrast, using the micropatterned electrode, only pinprick sensations were produced by the stimulation of the hairy skin, while the stimulation of the glabrous skin produced no sensation at all within the limits of stimulation intensities used in this study.
Conclusions
Using the CO2 laser or the micropatterned electrode, pinprick sensations were selectively produced by the stimulation of hairy skin, while only warm sensation or no sensation at all were produced by the stimulation of glabrous skin. These two techniques appear to be more selective with a limited diffusion of the stimulation into the skin, restricting the activation of sensory afferents to the most superficial and smallest intraepidermal nerve fibers.
Objective
In patients with chemotherapy-induced peripheral neuropathy (CIPN), demonstration of small fibre (SF) damage is important to understand chronic late effects.
Methods
Thirty patients having complaints compatible with possible CIPN following treatment with oxaliplatin or docetaxel were compared with 27 healthy subjects. All subjects were evaluated with quantitative sensory testing (QST) assessing SF function and laser evoked potentials (LEP). In addition, SF-damage was assessed using cutaneous silent periods evoked with electrical (El-CSP) and laser (Ls-CSP) stimuli.
Results
For LEP, N2P2 amplitudes were significantly smaller in patients than controls in both upper (P=0.007) and lower extremities (P=0.002), and the N1 amplitude in upper extremities of patients were significantly smaller than in controls (P= 0.001). SF-QST, LEP, Ls-CSP, and El-CSP were abnormal in 10 (33.3%), 16 (53.3%), 19 (63.3%), and 24 (80%) of CIPN patients, respectively.
Conclusions
In patients with possible CIPN, El-CSP and Ls-CSP were more often abnormal than LEP and QST. This is probably because El-CSP and Ls-CSP inform mainly about peripheral nociceptive fibres, while LEP and QST inform about peripheral and central nociceptive pathways together.
Significance
LEP and QST are established methods to detect SF-damage. El- and Ls-CSP might help clinicians in diagnosing SF-damage.
To prevent pain associated with 8% capsaicin application, pretreatment with local anesthetics, such as EMLA (eutectic mixture of lidocaine 2.5% and prilocaine 2.5%), is considered an option. However, there is contradicting evidence regarding the effects of local analgesia on capsaicin-induced desensitization. In session 1, two skin areas in each forearm of 24 healthy volunteers were randomized to 2-hour pretreatment with EMLA/placebo cream. After pretreatment, 8% capsaicin patches were applied for 3 hours in one placebo and one EMLA pretreated area, obtaining the following four areas: Capsaicin+EMLA, Capsaicin+Placebo, EMLA alone, and Placebo. Pain intensity scores were assessed during the 3-h application of capsaicin. Warmth detection, heat pain sensitivity, and micro-vascular reactivity were measured after the removal of capsaicin. After 24 hours, in session 2, all tests were repeated followed by histamine application in each area to examine itch intensity and neurogenic flare.
Overall, EMLA caused significant reductions in capsaicin-induced pain compared with placebo (p=0.007) and enhanced the capsaicin-induced increase in superficial blood perfusion immediately after the 3-hour capsaicin application (p<0.01). Regardless of pretreatment, capsaicin induced heat hyperalgesia immediately after the application (p<0.001). 24 h post application, heat pain sensitivity was normalized. However, WDT increased significantly (p<0.001). Capsaicin tended to reduce the itch intensity and significantly reduced the neurogenic flare (p<0.05) induced by histamine compared with EMLA alone. The findings suggest that pre-treatment with topical analgesic cream reduces application site pain without interfering with the 8% topical capsaicin-induced desensitization.
Perspective: Pretreatment with local anesthetic EMLA cream might be considered a good therapeutic option to reduce the pain associated with 8% capsaicin application currently used for treatment of neuropathic pain syndromes. This study also suggests the existence of a synergistic effect of capsaicin and EMLA on the process of neurogenic inflammation.
Background
A noxious stimulus following a more intense stimulus often feels less painful than continuous noxious stimulation. This effect, known as offset analgesia (OA), may be due to descending inhibitory control, to changes in peripheral neural transmission, or both. The timing and location of noxious thermal stimulation were manipulated to better understand the peripheral and central contributions to OA.
Methods
In a first experiment, participants (n=29) provided continuous pain ratings as stimuli were delivered to the palm or dorsum of each hand. Offset trials included 44 °C (T1), 45 °C (T2), and 44 °C (T3) stimulation periods. Baseline trials were identical except the T3 temperature fell to 35 °C. Constant trials were 44 °C throughout. The duration of T1 and T2 was either 1s or 6s, whereas T3 was always 12s. In a second experiment, participants (n=43) rated pain levels of noxious stimuli presented to the forearms with varying T1 and T2 durations (3, 6, 10 or 13s) and a 20s T3 period.
Results
OA effects became stronger with increasing inducing durations. OA, however, was not found on the palm even at longer durations.
Conclusions
The increase of OA with duration suggests that accumulated nociceptive signalling is more important to triggering OA than is a decrease in nociceptors’ instantaneous firing rates. The lack of OA on the palm, however, implies a key role for the rapidly adapting Type II AMH fibres that may be absent or not readily activated on the palm. Unravelling the relative central and peripheral contribution to OA requires further investigation.
When a rate histogram is used to represent the firing pattern of a neuron there is the potential for serious error due to aliasing, and because of this the rate histogram is a very poor way to represent neural activity. It is theoretically possible to encode a signal in a spike train and decode it without error by filtering and sampling. There is no natural optimal filter design for this problem, but it is possible to specify the characteristics of a good rate estimating filter heuristically and design a filter with these characteristics. Two rate estimating filters are described here. Their performance has been tested, and compared to the rate histogram and the French-Holden rate estimating algorithm, by measuring their ability to recover signals encoded as impulse sequences by Integral Pulse Frequency Modulation (IPFM). These filters are simple to implement and perform well. They should be used in preference to the rate histogram.
We recorded laser-evoked potentials (LEPs) from 20 normal subjects by stimulating the skin with pulses from an infrared CO2 laser. The conduction velocity of the peripheral afferent fibers mediating the LEPs averaged 14.9 m/sec. The amplitude of the LEP components correlated significantly with perceived stimulus intensity. During repetitive constant intensity stimulation, the peak-to-peak LEP amplitude decreased 38% during a distraction task and 42% during drowsiness and was absent during stage 2 sleep, indicating a modulation of responsiveness to laser stimulation during distraction and decreased states of arousal. Normative data revealed considerable intersubject variability in LEP latencies and amplitudes. Analysis of intrasubject lateralized (side-to-side) differences revealed that the relative peak-to-peak amplitude was less variable than that of the N or P components. For clinical applications using 3 S.D.s to define the normal range, a lateral interpeak amplitude difference greater than 28% would suggest focal or lateralized sensory abnormality in an individual patient. Vigilance and attentiveness to the stimuli should be monitored during the acquisition of LEPs.
Conduction velocity of A delta fibers of the human peripheral nerves was measured by using pain-related somatosensory evoked potentials following CO2 laser stimulation. It was found to be approximately 9 m/s in the forearm as well as in the lower leg. Because conventional conduction study using electric stimulation reflects only functions of large myelinated fibers related to deep proprioceptive and tactile sensations, the present noninvasive and simple, novel method is the only laboratory examination currently available to investigate physiological functions of the small diameter fibers mediating pain-temperature sensations.
The latency to detection of heat stimuli applied to the distal forearm and thenar eminence was measured in 3 subjects in order to determine whether short latency responses correlated with perception of first pain. Only one temperature was used in a given run and stimuli ranged from 39 to 51 °C. In addition, subjects were interviewed at the end of each run regarding the quality of sensations experienced. In one series of experiments the quality of the first sensation evoked by each stimulus rather than latency was recorded. The median response latency decreased exponentially from 1100 ms to 400 ms for the distal arm and 1100 ms to 700 ms for the hand. The higher temperatures elicited a double pain sensation on the arm, but not on the glabrous hand. Warmth was always the first sensation felt on the hand. It is concluded that short latencies (less than 450 ms) reliably denote the presence of first pain, and that at least some portion of the primary afferents that signal first pain must have conduction velocities greater than 6m/s.
A problem in the study of nociceptors is that intense stimuli are used to locate the receptive field (RF), and thus the receptor may be damaged before the first responses are recorded. In addition, some nociceptors do not respond to the mechanical stimuli often used to search for the RF. To overcome these problems, an electrical search technique was developed to locate the RF of cutaneous nociceptors. In the hairy skin of anesthetized monkey, we used this technique to locate the RF of 63 Aδ-fibers and 22 C-fibers that had extremely high thresholds or were unresponsive to mechanical stimuli. We refer to these afferents as mechanically insensitive afferents (MIAs). Ten Aδ-fiber MIAs had a short latency response to stepped heat stimuli and could be responsible for first pain sensation. Five Aδ-fiber MIAs and one C-fiber MIA did not respond to mechanical or heat stimuli but did respond to injection into the electrical RF of an artificial inflammatory soup containing histamine, bradykinin, prostaglandin E1, and serotonin. These chemoreceptors might be responsible for the pain and itch sensations that result from chemical stimuli. Some MIAs became more responsive to mechanical stimuli after injection into the RF of the inflammatory soup and, thus, may contribute to the hyperalgesia to mechanical stimuli associated with cutaneous injury. A large proportion of the Aδ-fiber (48%) and C-fiber (30%) afferents in this study were insensitive to mechanical stimuli. The role of these MIAs in sensation needs to be studied further. The electrical search technique enables a systematic study of these afferents to be performed. This technique may also be of use to identify and characterize dorsal horn neurons that have inputs from MIAs.
We sought to determine the effects of a cut injury on the thermal responsiveness of C-fiber nociceptors sensitive to heat and mechanical stimuli (CMHs). Teased fiber techniques were used to record from single CMHs that innervated the hairy skin of the monkey arm. Responses to heat stimuli ranging from 41 to 49°C were compared before and after injury. In 11 CMHs, the injury was applied 4 mm peripheral to the edge of the receptive field. The response to the heat sequence was not significantly altered by this adjacent injury. In 16 CMHs, a cut was applied directly to the receptive field. This direct injury led to a significant increase in response to the sequence of heat stimuli (i.e., sensitization). It is concluded that spreading sensitization of C-fiber nociceptors to a cut injury does not occur in monkey.
Forty-four myelinated primary afferents innervating the monkey hand and sensitive to both mechanical and heat stimuli (AMHs) were studied by the method of single-unit recording. The thermal response properties were studied with use of a noncontact laser thermal stimulator that provided step increases in skin temperature with rise times of 200-250 ms and temperature control within 0.1°C. Mechanical response properties were studied with use of a stimulator that provided step increases in force. The AMHs had a mean conduction velocity of 31.1 ± 1.5 (SE) m/s (range 5.2-53.3 m/s), mean receptive-field area of 37±4 mm2 (range 2.3-121 mm2), a mean pressure threshold of 3.5±0.3 bars (Von Frey technique' range, 1.6-9.4 bars), no response to cooling stimuli, and no spontaneous activity prior to stimulation. The number of impulses evoked by mechanical stimulation with a 0.8 mm-diameter probe increased monotonically with increasing force of skin identation up to 200 g, the highest force used. Each of the AMHs became sensitized to heat after repeated exposure of its receptive field to high intensities of heat. When a 53°C stimulus of 3 s duration was delivered every 28 s, the number of impulses evoked during each stimulus increased, the response latency decreased, the duration of the afterdischarge and the number of impulses in the afterdischarge increased, and spontaneous activity frequently developed. Before sensitization, 88% (37 of 42) had heat thresholds greater than 49°C. After sensitization the heat thresholds were lower for all fibers tested (n=30) and 67% had thresholds less than 45°C. The number of impulses evoked by suprathreshold stimuli increased monotonically with stimulus temperature. The response properties of AMHs were compared with those of polymodal nociceptive C-fibers (CPNs) that innervated the monkey hand. The receptive fields of 12 CPNs were exposed to 53°C stimuli of 3 s duration delivered every 28 s. In contrast to the AMHs, all but one CPN showed response depression as a function of iterative stimulation. The response properties of AMHs were compared with those of eight slowly adapting mechanoreceptive afferents (SAMs) that innervated the monkey hand. The pressure threshold (̄x, 1.09 bars) was significantly less and the conduction velocity (̄x, 42.6 m/s) and receptive-field area (̄x, 65.8mm2) significantly greater than corresponding values for the AMHs. In contrast to AMHs, SAMs responded only during the cooling phase of heat stimuli. This thermal response increased with iterative heating and thus, is considered a special form of sensitization. AMHs are a distinct population of mechanically sensitive cutaneous nociceptive afferents that develop a prolonged increased sensitivity to heat following noxious heating of their receptive fields. Thus, hyperalgesia that follows a cutaneous burn may be mediated, at least in part, by activity in AMHs.
1. Radiant-heat stimuli of different intensities were delivered every 28 s to the thenar eminence of the hand of human subjects and to the receptive fields (RFs) of 58 "mechanothermal nociceptive" and 16 "warm" C-fibers, most of which innervated the glabrous skin of the monkey hand. A CO2 infrared laser under control via a radiometer provided a step increase in skin temperature to a level maintained within +/- 0.1 degrees C over a 7.5-mm-diameter spot. 2. Human subjects categorized the magnitude of warmth and pain sensations evoked by stimuli that ranged in temperature from 40 to 50 degrees C. The scale of subjective thermal intensity constructed from these category estimates showed a monotonically increasing relation between stimulus temperature and the magnitude of warmth and pain sensations. 3. The mechanothermal fibers had a mean RF size of 18.9 +/- 3.2 mm2 (SE), a mean conduction velocity of 0.8 +/- 0.1 m/s, mean thresholds of 43.6 +/- 0.6 degrees C for radiant heat and 5.95 +/- 0.59 bars for mechanical stimulation, and no spontaneous activity. In contrast, warm fibers had punctate RFs, a mean conduction velocity of 1.1 +/- 0.1 m/s, heat thresholds of less than 1 degrees C above skin temperature, no response to mechanical stimulation, and a resting level of activity in warm skin that was suppressed by cooling. 4. The cumulative number of impulses evoked during each stimulation in the nociceptive afferents increased monotonically as a function of stimulus temperature over the range described by humans as increasingly painful (45-50 degrees C). Nociceptive fibers showed little or no response to stimulus temperatures less than 45 degrees C that elicited in humans sensations primarily of warmth but not pain. In contrast, the cumulative impulse count during stimulation of each warm fiber increased monotonically with stimulus temperature over the range of 39-43 degrees C. However, for stimuli of 41-49 degrees C the cumulative impulse count in warm fibers was nonmonotonic with stimulus temperature. Warm-fiber response to stimuli of 45 degrees C or greater usually consisted of a short burst of impulses followed by cessation of activity. 5. The subjective magnitude of warmth and pain sensations in humans and the cumulative impulse count evoked by each stimulus in warm and nociceptive afferents varied inversely with the number, delivery rate, and intensity of preceding stimulations. 6. The results of these experiments suggest the following: a) that activity in the mechanothermal nociceptive C-fibers signals the occurrence of pain evoked by radiant heat, and that the frequency of discharge in these fibers may encode the intensity of painful stimulation; b) that activity in warm fibers may encode the intensity of warmth at lower stimulus temperatures, but is unlikely to provide a peripheral mechanism for encoding the intensity of painful stimulation at higher stimulus temperatures.
1. Experiments were carried out to investigate the mechanism whereby thermal stimul excite nerves to produce pain from teeth. 2. Recordings have been made from single fibres dissected from the inferior dental nerve in dogs during thermal stimulation of the lower canine tooth. 3. In preliminary experiments, no units were found with thresholds close to the thresholds for pain in man (45 and 27 degrees C) and subsequently test stimuli of 55 degrees C, applied for up to 15 sec, and 0-5 degrees C were used. 4. Of 117 fibres tested, forty-three responded to cooling but not to heating and nine responded to heating but not to cooling. 5. By applying thermal stimuli direct to the saphenous nerve in cats, it was shown that these responses might have been due to direct excitation of nerves and not to stimulation of specialized receptors. 6. Some units responded to electrical stimulation of the tooth pulp with a latency which decreased abruptly at a critical intensity as the stimulus was increased above threshold. Evidence was obtained which suggested that this was due to branching of the fibres.
1. Seventy high threshold mechanoreceptor units (HTMs) with myelinated axons were isolated from the sural nerves of cats and rabbits. Thirteen cat and forty-two rabbit HTMs were testec by controlled, repeated heating of the skin of the foot or lower leg to noxious levels. 2. Many of the units (77% in the cat and 40% in the rabbit) fired to heating. Only six (11%) of these fired to the first brief heating to 50-55 degrees C. The rest required 2-6 heat trials before responding. 3. Heat responding units always became more sensitive with repeated heat stimulation but their mechanical sensitivity showed no comparable changes when heat sensitization occurred. 4. If these results are applicable to man, they suggest that HTMs play little role in generating the first pain that follows skin heating but that they may be involved in the increased sensitivity to heat pain (hyperalgesia) shown by skin previously injured by heating.
Hyperalgesia after cutaneous injury can be divided into two phenomena: Primary hyperalgesia occurs at the site of injury and is characterized by hyperalgesia to mechanical and heat stimuli. Secondary hyperalgesia occurs outside the injury site and is characterized by mechanical hyperalgesia only. Hyperalgesia in inflammatory processes corresponds to primary hyperalgesia. Hyperalgesia in referred pain and neuropathic pain resembles secondary hyperalgesia (Table 3). Evidence for the latter would be strengthened if hyperalgesia to cooling stimuli, which is observed in neuropathic pain, was also demonstrated in referred pain and in secondary hyperalgesia. Some of the more likely neural mechanisms to explain primary and secondary hyperalgesia are illustrated in Fig. 8. Primary hyperalgesia to heat stimuli has a counterpart in the sensitization of peripheral nociceptors to heat stimuli (Fig. 8A), leading to similar changes in central neurons. In addition, the enlargement of the mechanical receptive field of primary afferent nociceptors to include the site of injury may account for the primary hyperalgesia to mechanical stimuli (Fig. 8B). In the literature, there are some contradictions with respect to the stimulus modalities to which hyperalgesia and sensitization occur. In spite of the well-documented sensitization of primary afferent nociceptors to heat stimuli, there are few studies on its molecular mechanisms. On the other hand, there is pharmacological evidence for a peripheral mechanism of primary mechanical hyperalgesia, but little direct evidence that nociceptors can be sensitized to mechanical stimuli by injury. This contradiction should spawn further investigations into the mechanical response properties of nociceptors and into the molecular mechanisms of heat sensitization. Secondary hyperalgesia to mechanical stimuli is likely due to the sensitization of central pain signalling neurons (CPSNs). This sensitization could involve only input from nociceptors (Fig. 8C), since mechanical pain thresholds after a cutaneous injury are of the same order as those of nociceptors. Central sensitization could also be the result of enhanced connectivity between low-threshold mechanoreceptors and CPSNs (Fig. 8D). This form of sensitization may account for the pain to light touch associated with neuropathic pain. Receptive field plasticity is a prevalent property of dorsal horn neurons and probably plays a vital role with regard to hyperalgesia. The molecular mechanisms of synaptic plasticity are currently subject to intense experimental investigation and may provide new insights on the mechanisms of pain and hyperalgesia.
The differences in excitability along geometrically inhomogeneous, electrically excitable structures as well as the possibility of occurrence of "hot spots" at certain branch points were theoretically analysed on the basis of the Hodgkin-Huxley model assuming uniform specific membrane parameters along the structure length. It was shown that the "hot spots" conditioned by geometrical inhomogeneities should be not only morphological but also functional formations. The excitability at the branch point could be higher than that at the rest of the structure when the branch point was an electrical equivalent of a step decrease in the cable diameter. The stronger the diameter decrease, the higher the excitability at the branch point and thus the higher is the possibility of observation of "hot spots" in the nerve cells whose dendrites have a profuse branching. The realization of the "hot spots", however, depended on the distance from the site of the stimulus application (synapse) to the branch point and on the stimulus (synaptic current) strength, as well. The closer the synaptic current strength to the threshold value, and the shorter the synapse-branch point distance, the higher was the possibility of a propagating action potential origin at the branch point but not at the site of the stimulus application and thus the higher was the possibility of realization of "hot spots". The conclusion that the geometrical position of the initial segment contributes to its higher excitability (as compared to the rest of the cell) in the case of orthodromic activation of the neuron was also made.
1. The proportion of primary afferent nerve fibres in a skin nerve of the rat that responded or failed to respond to mechanical or thermal stimulation of the skin in the noxious and non-noxious range was analysed. 2. Activity of afferent nerve fibres was recorded from the dorsal roots. Units projecting into the sural nerve were selected using supramaximal electrical stimulation of the nerve stem. All other hindleg nerves were cut. 3. The receptive fields were searched by carefully examining the hindleg skin with noxious and innocuous mechanical, cooling and warming stimuli. Probing of the intrinsic foot muscles and manipulation of the ankle and toe joints was employed to recruit units projecting to deeper tissues. 4. In a first series of twenty-two experiments, eighty-nine rapidly conducting myelinated A beta units, thirty slowly conducting myelinated A delta units and 101 unmyelinated C units were investigated. Most units were identified as belonging to one of the established classes of cutaneous sensory units and this was also ascertained by a collision test. 5. Two A beta, eight A delta and forty-six C fibres did not respond to any one of the stimuli. Electrical thresholds and conduction velocities of the unresponsive C fibres were not significantly different from those of the units responding to natural stimulation of their receptive fields. In the A delta group unresponsive and high threshold mechanoreceptive units were preferentially found among the units with the slowest conduction velocities. 6. In a second series of seven experiments, one single nerve filament containing responsive and unresponsive C fibres was tested repetitively at 30 min intervals. Twenty unresponsive units and seven units responding to noxious mechanical and/or heat stimuli were studied. Ten of the twenty initially unresponsive units became activated by mechanical and/or heat stimuli after observation times of 30-150 min. Some of these units had mechanical thresholds as low as 64 mN (tested with calibrated von Frey hairs), or thermal thresholds down to 42 degrees C. 7. Two of the ten C units which became responsive in the course of an experiment later lost their responsiveness again. On the other hand, two of the C units which were initially responsive to noxious heat and/or noxious mechanical stimuli became completely unresponsive after repetitive stimulation, whereas one unit initially only responding to noxious heat became responsive to mechanical stimuli, suggesting that mechanical and heat responsiveness may be separately gained or lost by sensory C fibres.(ABSTRACT TRUNCATED AT 400 WORDS)
1. Receptive-field properties were investigated in cutaneous C-fiber nociceptive afferents (CMH) responsive to mechanical and heat stimuli. Teased-fiber techniques were used to record from 28 CMHs that innervated the hairy skin of upper or lower limb in anesthetized monkeys. 2. The response to mechanical stimuli was studied with the use of calibrated von Frey probes. The response to heat stimuli was studied with the use of a laser thermal stimulator that provided stepped increases in skin temperature with rise times to the desired temperature near 100 ms. The size of the receptive field (RF) for mechanical stimuli was determined by use of a suprathreshold stimulus that consisted of a 0.5-mm-diam probe that exerted a 200-mN force (10 bar). The size of the heat RF was determined by use of a 49 degrees C stimulus applied to a 7.5-mm-diam area for 1 s. 3. Heat thresholds were determined with an ascending series of stimulus intensities and were found to be stable over many hours: they ranged from 37 to 46 degrees C (mean, 41.1 degrees C). Mechanical thresholds ranged from 1.3 to 7.3 bar (mean, 3.3 bar). There was no correlation between mechanical and heat thresholds. Both thresholds extended well below the corresponding psychophysical pain thresholds in the literature. This suggests that spatial and/or temporal summation of C-fiber input are important for pain induced by either stimulus modality. 4. Mechanical RF diameters ranged from 3.3 to 9.6 mm (mean, 4.7 mm); heat RF diameters ranged from punctate (less than 1 mm) to 9.5 mm (mean, 4.3 mm). There was a significant linear correlation between mechanical and heat RF sizes with a slope of one. The distance between the center of the mechanical RF and the center of the heat RF along one axis ranged from 0 to 1.1 mm (mean, 0.4 mm). These data indicate that the heat RFs coincided with the mechanical RFs. 5. Within the mechanical RF determined with the suprathreshold stimuli, all CMHs had one or more punctate areas of maximal mechanical sensitivity where mechanical threshold was lowest. Heat excitability extended greater than 2 mm beyond these mechanically sensitive spots. Because lateral transmission of the heat stimulus is small, this indicates that heat transduction occurs outside the regions of maximal mechanical sensitivity. 6. Both the threshold to heat and the response magnitude at suprathreshold intensities depended on the percentage of the RF area overlapped by the heat stimulus. This indicates that multiple transducer sites probably contribute to the total evoked response.(ABSTRACT TRUNCATED AT 400 WORDS)
1. Properties of sensory receptors with slowly conducting nerve fibers (less than 10 m/s) were studied using a rat skin-saphenous nerve in vitro preparation where receptive fields of identified single units can be isolated and superfused at the corium side with defined chemical solutions. 2. With mechanical search stimuli, 150 slowly adapting units were identified, 88% C-fibers, and the remainder, A delta-fibers. The majority of these units (65%) were categorized as mechano-heat sensitive ("polymodal") with controlled radiant heat stimulation. The remaining units were classified as low- or high-threshold mechanoreceptors according to their von Frey thresholds. 3. Bradykinin (BK), in concentrations of 10(-8) to 10(-4) M, was repeatedly applied for 1 min at 10-min intervals. Fifty-six percent of the polymodal C-fibers responded to BK (up to 10(-5) M), in contrast to 17% of the heat-insensitive units (P less than 0.01). No correlation between BK sensitivity and conduction velocity or von Frey threshold was found. 4. The BK "threshold concentrations" to excite C- and A delta-fibers were about equally distributed over a range from 10(-8) to 10(-5) M. 5. There was a large interindividual variability in pattern and magnitude of the response to BK. Intraindividually, a marked tachyphylaxis upon repeated BK stimulation was observed. 6. In fibers with a slow development of tachyphylaxis, the effects of conditioning application of different chemicals on BK responsiveness were studied. Norepinephrine in 10(-7) M concentration did not produce a significant effect, whereas 10(-5) M and 10(-4) M seemed to increase the BK responses. 7. Prostaglandin E2 (10(-6) M) caused a weak sensitization to BK on average (n.s.), but serotonin (10(-6) M) was clearly effective (P less than 0.05). 8. The strongest sensitization to BK (P = 0.01) resulted from conditioning heat stimulation, which also uncovered a responsiveness in some units initially insensitive to BK. 9. In some experiments the calcium concentration in the superfusate of receptive fields was lowered to 0.3 mM, which induced ongoing activity in C-fibers and markedly increased the BK responses in two polymodal units tested. Increasing the calcium concentration to 3.0 mM reversed these effects. 10. After completing the BK test protocol, polymodal C-fibers were exposed to other chemicals.(ABSTRACT TRUNCATED AT 400 WORDS)
Late components of cerebral potentials evoked by brief heat pulses applied to various skin sites were used to monitor the afferent pathways of pain and temperature sensitivity. Radiation at 10.6 micron wave length generated by a CO2 laser stimulator predominantly activates superficial cutaneous A delta and C nociceptors and elicits late and ultralate cerebral potentials. This paper deals with the investigation of the component structure and topography of the A delta fibre mediated late potentials, which were compared with the corresponding late potentials in response to standard electrical nerve stimuli. In the upper limb both stimulus types evoked a large positive potential (nerve: 260 msec, skin: 390 msec latency), preceded by a negativity (nerve: 140 msec, skin: 250 msec). Whereas these components were always maximal at the vertex, an earlier negativity appeared over the somatosensory projection area (nerve: 70 msec, skin: 170 msec). After stimulation of the lower limb all latencies were delayed by 20-30 msec. As a rule, the heat-evoked potentials appeared about 100 msec later than the corresponding potentials after electrical nerve stimulation. Similarities in interpeak latencies and scalp topography indicated similar cerebral processing.
The authors recorded cerebral-evoked responses elicited by direct stimulation of the human lateral spinothalamic tract (LST) during percutaneous cordotomy to investigate central conduction of noxious stimuli. These responses consisted of four negative potentials, peak latency being 3.8 (N1), 8.4 (N2), 12.2 (N3) and 21.9 (N4) ms respectively. N1 showed wide distribution over the scalp and was considered to be of subcortical origin. N2-N4 were distributed in both the temporal and central area. The different distribution pattern of N2-N4 from conventional somatosensory-evoked potential suggested a different projection of LST from the medial lemniscus system.
Brief CO2 laser radiant heat pulses activate both A delta- and C-fibres. In the evoked potential (EP) late and ultralate components can be seen as correlates of first and second pain. Usually the ultralate EP appears to be suppressed. It could be uncovered by a preferential A-fibre block, and in two neurological patients with tabes dorsalis and with a polyneuropathy involving myelinated fibre loss. Due to a strong latency jittering the shape of the ultralate component is distorted in the conventional average. Latency corrected averaging, adaptive filters or parametric spectral estimators are needed to analyze these EP components. As a result the filtered ultralate waveforms look very similar to the late EP components. Clinical application of CO2 laser EPs promises to nonivasively assess A delta- and C-fibre function.
Data analyzed in this study were derived from the responses of 128 spinothalamic tract (STT) cells and 110 thalamic neurons recorded in 75 anesthetized monkeys. A k-means cluster analysis, a nonhierarchical clustering technique, was performed using the relative magnitudes of responses to a graded series of innocuous and noxious mechanical stimuli applied to the receptive field. For comparison, a parallel analysis was performed based on definitions of low-threshold (LT), wide dynamic range (WDR), and high-threshold (HT) cells used by our laboratory. For 128 STT cells, a classification scheme with three clusters was found statistically to be the best. This yielded groups of 22, 57, and 49 cells in clusters 1, 2, and 3, respectively. Cluster 1 cells were activated best by low-intensity mechanical stimuli, whereas cluster 3 cells were activated primarily by nociceptive stimuli. Cluster 2 cells had intermediate characteristics. When the classification scheme based on the cluster analysis was compared with the classification of the same neurons as LT, WDR, and HT cells, cluster 1 cells were divided into LT and WDR cells, whereas cluster 2 and 3 cells included WDR and HT cells. For 110 thalamic neurons, a classification scheme with five clusters was found statistically to be the best. Clusters 1-5 contained 25, 34, 17, 10, and 24 cells, respectively. Response characteristics of cells in each group indicated a gradual change in sensitivity to higher intensities of peripheral input from cluster 1 to 5. When this classification scheme was compared with the classification scheme previously used by our laboratory, cluster 1 cells belonged to the LT group, clusters 2 and 3 split into LT and WDR cells, and clusters 4 and 5 included WDR and HT cells. It is concluded that a classification scheme based on a cluster analysis of the responses of neurons to standardized stimuli may provide an objective and functionally meaningful way to categorize somatosensory neurons.
1. The functional characteristics of cutaneous receptors in the squirrel monkey were determined by recording discharges of single myelinated afferent fibres in peripheral nerves with micro‐electrodes or from fine filaments prepared by dissection. One hundred and sixty‐nine fibres of the posterior femoral cutaneous nerve and 209 of the superficial radial nerve with conduction velocities between 4 and 88 m/sec were classified according to the nature of the most effective stimulus, discharge characteristics, adaptation rate and organization of the receptive field.
2. Twenty per cent of the fibres innervating either hairy or glabrous skin required strong mechanical stimuli for activation; thresholds ranged from moderate to overtly damaging pressures. This class showed little or no sensitivity to thermal changes including noxious heat. Their receptive fields consisted of numerous, mechanically‐excitable points or spots. All such fibres gave higher impulse frequencies to noxious than to innocuous mechanical stimuli and a large fraction were considered to be nociceptors because they responded only to noxious deformation. The conduction velocities of nociceptors were distributed between 5 and 28 m/sec.
3. All but a few of the other fibres encountered responded vigorously to innocuous stimuli and were readily identified as corresponding to one of the receptor types known to exist in either the primate or the cat. These sensitive receptors were systematically tested by intense cutaneous stimuli; their response to injurious stimuli always could be mimicked by innocuous ones.
4. Therefore, in the primate a particular class of slowly‐conducting myelinated fibres is partially responsible for signalling mechanically‐induced cutaneous damage. The probable relation between such afferent fibres and certain kinds of cutaneous pain is explored.
1. Ninety-six C-fiber nociceptive afferents responsive to both mechanical and heat stimuli (CMHs) were studied in the monkey in an effort to determine what stimuli cause sensitization. Thirty-two of the fibers innervated glabrous skin (G-CMHs), while 64 innervated hairy skin (H-CMHs). Single-unit recording techniques were used. 2. The response to heat stimuli was studied with use of a laser thermal stimulator that provided stepped increases in skin temperature over a 7.5-mm-diameter area with rise times to the desired temperature near 100 ms for each stimulus. Changes in sensitivity were studied with a thermal test sequence (TTS), which consisted of 10 3-s stimuli presented with a 27-s interstimulus interval. The first stimulus was always 45°C. The remaining nine stimuli ranged from 41 to 49°C in 1°C increments and were presented in random order. The effects of stimulation with a more intense stimulus, 53°C for 30 s, were also determined. 3. The TTS stimuli were presented multiple times to the same fiber with a 10-min stimulus-free interval between runs. The H-CMHs were sensitized by the TTS stimuli, while the G-CMHs were not. Sensitization in the H-CMHs was manifest by a significant increase in the mean cumulative response to successive TTS stimuli, a significant decrease in thermal threshold, a significant increase in response to the first stimulus of each TTS run (viz., 45°C), and the development of spontaneous activity in certain of the H-CMHs. These changes in responsiveness were not observed in the G-CMHs. 4. Presentation of more intense stimuli (53°C for 30 s) caused further sensitization in many of the H-CMHs, but the effect was not significantly different from the change evoked by presentation of the TTS stimuli. The G-CMHs did not sensitize to the 53°C, 30-s stimulus (burn), and in most fibers suppression occurred, as measured by the response to the TTS stimuli 10 min after the burn. The suppression tended to be less marked 25 min after the burn. 5. The difference between H-CMHs and G-CMHs cannot be explained by a difference in the initial sensitivity of the two types of fibers. The mean responses to the initial 45°C stimulus of the first TTS run were similar: 10.3 ± 1.3 (SE) impulses for G-CMHs, and 9.8 ± 1.8 impulses for H-CMHs. The thermal thresholds, as measured by the response to the first TTS run, were also similar: 44.3 ± 0.3°C for G-CMHs, and 44.6 ± 0.2°C for H-CMHs. 6. The increased response to the TTS stimuli over successive runs for the H-CMHs tended to reach a plateau by the fourth run. The additional application of the burn in a few of these fibers failed to increase the response to TTS stimuli further. 7. In 10 H-CMHs, the duration of the TTS stimuli was changed from 3 to 1 s and runs were repeated after 10-min stimulus-free intervals. In contrast to the increased response evoked by 3-s stimuli, the mean response of the H-CMHs to the 1-s stimuli did not change significantly over successive runs. 8. Alhough the H-CMHs showed sensitization from one run to the next, within a run only suppression was evident. For example, the response to the second 45°C stimulus of the TTS in the first run was 31 ± 5% of the response evoked by the first 45°C stimulus within the same run. 9. The conduction velocity and receptive-field size of the H-CMHs and G-CMHs did not differ. However, the mechanical threshold of the H-CMHs (2.51 ± 0.11 bars) was significantly less than that of the G-CMHs (4.27 ± 0.32 bars, P<0.001). 10. It is concluded that H-CMHs and G-CMHs differ significantly with regard to the propensity to sensitize to noxious heat stimuli. H-CMHs sensitize readily, and G-CMHs given the same stimuli do not sensitize. These results suggest that C-fiber nociceptive afferents do not play an important role in hyperalgesia in glabrous skin but may play an important role in hyperalgesia in hairy skin. This finding also supports the hypothesis that A-fiber nociceptive afferents play an important role in explaining the marked hyperalgesia that is produced by a substantial thermal injury (52°C for 30 s) to the glabrous skin of the hand.
The receptive properties of A-δ-fibers were studied in young healthy volunteers by single-fiber recording from the cutaneous branch of the radial nerve. Mechanical stimulation was performed with a set of von Frey hairs. Response to cooling was tested with ether or ice. A feedback-controlled radiant-heat stimulator delivered heat pulses at different temperatures, ranging from 37 to 46.5°C. A paint-removing substance, containing methylene chloride in methanol, was used as a chemical irritant. The evoked sensation was registered by asking the subjects to report about their sensations and by cross-modality matching. The conduction velocity was computed in 140 A-δ-fibers (mean ± SD, 19.2 ± 7.2 m/s). The observed values corresponded well with the diameter distribution of thin myelinated fibers in the radial nerve of man. Mechanical threshold measurements in 66 A-δ-fibers revealed a low-threshold group (≤8.8 mN), which has some characteristics in common with the 'down hair receptors' found in animal experiments. The other fibers had high mechanical thresholds (≥22.5 mN) in the C polymodal nociceptor range. Twenty-one percent of those mechanoreceptive receptors were activated also by radiant heat. Responsiveness to heat usually seemed not to be a consequence of sensitization. The discharge frequency to radiant heat was higher in some A-δ-fibers than in C-fibers. A-δ-Fibers behaved differently from C polymodal nociceptors, since not all A-δ-fibers activated by chemical stimulation were responsive to radiant heat. Comparison of reported sensation and neural activity indicated that activation of an A-δ-fiber did not always coincide with a pain sensation. From these experiments the following conclusions were drawn. 1) There exist A-δ-fibers in the human similar to those described in other mammalian species. 2) A-δ-fibers with high mechanical threshold show a higher receptor specificity than C polymodal nociceptors. 3) The firing frequency on noxious stimulation is often higher in A-δ-fibers than in C-fibers.
Minimal conduction velocities of peripheral nerves contributing to acute thermal pain sensation in human volunteer subjects were calculated. Purely thermal stimulation was administered by a low power laser beam directed at the subjects' fingers, and subjective pain responses correlated with a peak in the event-related brain potential (ERBP). These cerebral responses were found to preclude C fiber peripheral activity from this phenomenon.
Short radiant heat pulses, emitted by a high power CO2 laser, were used to investigate single nociceptor activity, cerebral potentials and concomitant sensations. Stimuli of 20 and 50 ms duration with different intensities were randomly applied to the hairy skin of the hand. Microelectroneurography was performed from the radial nerve at the wrist; 26 stable recordings were evaluated. Pre- and post-stimulus EEG segments were recorded from vertex versus linked ear lobes. Sensation was assessed on an eight-step category scale, an adjective scale, and by reaction times. In some experiments an A-fibre block was applied in order to isolate C-fibre responses. The main results were: Short heat stimuli activate C-units. In addition one of two identified A delta-units responded. None of the 15 A beta-units investigated was activated by the heat pulses. Short heat stimuli evoked cerebral potentials having a main vertex positive component at about 400 ms. These potentials were ascribed to A delta-fibre input. Laser induced pain consisted of an immediate stinging component, followed by a burning pain which often lasted several seconds. Reaction time to first pain ranged from 400-500 ms. Weak laser stimuli induced non-painful sensations mostly of tactile character. High correlations were found between the number of spikes elicited by a given stimulus and the intensity of the evoked sensation. Intensity discrimination, as evaluated by measures of Signal Detection Theory, was better in the peripheral C-units than in the subjective ratings. If conduction of A-fibres was blocked by pressure, A delta-related cerebral potential components vanished.(ABSTRACT TRUNCATED AT 250 WORDS)
The peripheral neural contributions to the magnitude of pain sensations elicited by heat stimulations of the skin and the increased pain to heat following a mild heat injury to the skin were studied by comparing psychophysical measures of pain in humans with impulse activity elicited by heat in single nociceptive afferents in the monkey. Human subjects made continuous magnitude ratings of pain elicited by short-duration stimuli of 39-51°C delivered before and at varying intervals of time following a heat injury induced by a conditioning stimulus (CS) of 50°C and 100 s duration. The same stimuli were delivered to the receptive fields in hairy and glabrous skin of C-fiber and A-fiber mechanoheat nociceptors (CMHs and AMHs, respectively). For heat stimulations of normal skin, that is, uninjured skin stimulated prior to the CS, pain thresholds ranged from 41 to 49°C. For most subjects, magnitude scaling functions for pain relating the maximum rating of pain elicited by each stimulus to stimulus temperature were slightly positively accelerating. The median maximum pain rating increased as a positively accelerating function of stimulus temperature. Threshold responses of CMH nociceptors in normal skin ranged from 41 to 51°C, while those of AMH nociceptors were generally greater than 51°C. The intensity-response functions of CMH nociceptors relating the total number of impulses elicited by each stimulus to stimulus temperature varied in shape, but the mean intensity-response function increased as a positively accelerating function of stimulus temperature. Therefore, the mean number of impulses elicited in CMHs in hairy and in glabrous skin of the monkey increased linearly with the median pain ratings in humans for hairy and glabrous skin, respectively. Within 5-10 min after the CS, pain thresholds were lower, and magnitude ratings of pain elicited by suprathreshold stimuli were greater than pre-CS values (hyperalgesia). Parallel changes were seen in the increased responses and/or lowered thresholds (sensitization) of most CMHs. While threshold changes in most CMHs in both types of skin paralleled changes in pain threshold following heat injury, only CMHs in hairy skin and not those in glabrous skin were sensitized a sufficient amount to contribute to increased magnitude ratings of pain following the development of hyeralgesia. In hyperalgesic skin, the median maximum pain rating increased as a negatively accelerating function of stimulus temperature, with the greatest increases over normal in pain ratings occurring in response to stimuli of 43-45°C in hairy skin and 47-49°C in glabrous skin with little if any increase in the magnitude of pain elicited by the highest stimulus of 51°C. In contrast, the impulse discharges of most CMH nociceptors exhibited the greatest increases in response to stimuli of 47-49°C. Since, in addition, the overall amount of sensitization of glabrous skin CMHs was not significant, the increases in CMH responses following a heat injury to either type of skin were not in proportion to increases in magnitude ratings of pain at each stimulus temperature. Evidence from control experiments indicated it was unlikely that the magnitude scaling of heat pain in normal skin and the changes in magnitude scaling following the development of hyperalgesia after heat injury depended on activity in AMH nociceptors, low-threshold thermoreceptors, or regional changes in blood flow. The results of these experiments suggest that activity in CMH nociceptors is a major peripheral determinant of heat pain sensation in normal skin and also contributes to the hyperalgesia following heat injury to the skin. If the magnitude of heat pain in normal skin is coded in the mean impulse discharge of CMH nociceptors as the data suggest, then the same neural code, at least as revealed in the responses of nociceptors in the monkey, does not fully account for the magnitude of change in pain sensation in humans following mild heat injury. Candidate explanations for certain mismatches between human sensory and monkey neural events are discussed.
Percutaneous recordings from single nociceptive A delta- and C-fibers have been performed from the superficial radial nerves of conscious human subjects. Nociceptors were tested with a chemical irritant substance, which induced a burning sensation when applied to the intact skin. A comparison of the onset of spike discharges in nociceptors and the onset of the subjective burning sensation indicated that under the conditions of our experiments summation of input from nociceptors is needed in order to induce pain sensations. In particular, our results indicate spatial summation.
Thermal stimulation with intense pulses of CO2 laser radiation has recently come into use as a method for generating robust cerebral evoked responses in man. Because the heat transient involved (at least 200°C/s) is at least an order of magnitude greater than that of most conventional thermal stimulators, we checked whether or not there might be anomalous activation of fiber types other than the well known cutaneous thermoreceptors. Recordings were made from primary afferent fibers in the rat sciatic nerve and second order somatosensory cells in the dorsal horn. Most of the laser-sensitive afferent fibers sampled were C polymodal nociceptors with lesser representation of other thermoreceptor types. There were no instances in which low threshold mechanoreceptors or other nonthermal afferent fibers were engaged. We conclude that the advantages of infrared laser stimulation are not compromised by a loss of receptor specificity.
Monkeys and human subjects were exposed to a series of thermal stimuli before and after a 53 degrees C, 30-second burn to
the glabrous skin of the hand. The responses of C- and A-fiber nociceptive afferents in the monkeys and subjective responses
by the humans were compared. The burn resulted in increased sensitivity of the A fibers, decreased sensitivity of the C fibers,
and increased pain sensibility (hyperalgesia) in the human subjects.
The aim of this study was to compare cerebral evoked potentials following selective activation of A beta and A delta fibers. In 15 healthy subjects, A beta fibers were activated by electrical stimulation of the left radial nerve at the wrist. A delta fibers were activated by short painful radiant heat pulses, applied to the dorsum of the left hand by a CO2 laser. Evoked potentials were recorded with 15-27 scalp electrodes, evenly distributed over both hemispheres (bandpass 0.5-200 Hz). The laser-evoked potentials exhibited a component with a mean peak latency of 176 msec (N170). Its scalp topography showed a parieto-temporal maximum contralateral to the stimulus side. In contrast, the subsequent vertex negativity (N240), which appeared about 60 msec later, had a symmetrical scalp distribution. Electrically evoked potentials showed a component at 110 msec (N110), that had a topography similar to the laser-evoked N170. The topographies of the N170 and N110 suggest that they may both be generated in the secondary somatosensory cortex. There was no component in the electrically evoked potential that had a comparable interpeak latency to the following vertex potential: for N60 it was longer, for N110 it was shorter. On the other hand, in the laser-evoked potentials no component could be identified the topography of which corresponded to the primary cortical component N20 following electrical stimulation.
1. A total of 312 cutaneous afferent units identified in the rat foot as belonging to one of nine major types of sensory receptors were included in the present study. A natural stimulus set was defined to differentiate optimally among those receptor types according to the distinguishing response patterns that it produced. It included air puffs, 30- and 300-Hz sinusoids, 200-mN force indentation of the skin, 1.2- and 6-N compressions of a skin fold, cooling the skin by 5 and 20 degrees C, warming by 5 degrees C, and heating by 15 degrees C. 2. The responses to predefined stimuli of 188 units were subjected to multivariate statistical analyses. The responses of an individual unit were measured as the number of impulses evoked by 10 stimuli, each lasting 10 s. Additionally, the number of impulses occurring for 5 s after withdrawal of a 200-mN indentation (1 of the 10 stimuli) was counted. 3. In discriminant analysis, the 11 stimulus variables predicted fairly correctly the grouping of afferent units into nine predetermined receptor categories (175 of 188, 93.1%), indicating a powerful ability to discriminate among different receptor types. Using hierarchical cluster analysis, afferent unit data described by 11 variables were divided into clusters that well represented prior receptor categories (170 of 188, 90.4%), suggesting the reliable application of this procedure to the classification of newly recorded cutaneous sensory receptors. 4. Eleven variables were then reduced to 7 on the basis of the results of factor analysis (95% of variance accounted for). The seven variables corresponded to 1.2-N compression, heating the skin by 15 degrees C, cooling the skin by 20 degrees C, 30- and 300-Hz sinusoids, withdrawal of a 200-mN indentation, and air puffs. 5. The seven selected variables correctly assigned afferent units into five modality-based categories in the discriminant solution (177 of 188, 94.1%). In the cluster solution, afferent units described by the seven selected variables were divided into clusters, most of whose members were modality specific (176 of 188, 93.6%). 6. The results indicate that cutaneous receptors can be divided into modality-specific groups according to similarities in their responses to seven stimulus variables. It is proposed that the stimulus set developed here and multivariate statistical methods can be used as powerful tools for the functional classification of central somatosensory neurons.
In the present study, partial lesions of the lower thoracic spinal cord in rats anaesthetized with halothane and nitrous oxide were made in order to elucidate which of the spinal funiculi mediate a nociceptive C fibre input to SI. Field potentials evoked by noxious CO2-laser stimulation were recorded in the left SI. Nociceptive C fibre input from the right hindpaw to SI was propagated by the dorsal funiculi (DF) and the left and right lateral funiculi (LLF and RLF, respectively). Nociceptive C fibre input from the left hindpaw was propagated by LLF and RLF, but not DF. Input from the hindpaws mediated by LLF and RLF caused widespread surface positive potentials throughout most of SI, although potentials in the hindlimb area tended to be larger than those in other areas of SI. Input from the right hindpaw mediated by DF caused surface positive potentials mainly in the hindlimb area of SI. Intracortically, the field potentials reversed polarity in the superficial laminae and had maximal negative amplitudes in laminae III-IV (input transferred by DF and LLF) and in laminae V-VI (input transferred by LLF and RLF). It is concluded that there are multiple spinal pathways which can transfer information from cutaneous nociceptive C fibres to SI in the rat. These ascending pathways seem to activate partly different thalamo-cortical systems.
1. A large proportion of the cutaneous nociceptor population in monkey either does not respond to mechanical stimuli or has very high mechanical thresholds (> 6 bar). The goal of this study was to determine whether these mechanically insensitive nociceptive afferents (MIAs) differ from mechanically sensitive nociceptive afferents (MSAs) with regard to responses to chemical stimuli. 2. Teased-fiber techniques were used to record from 28 A delta-fiber (16 MIAs and 12 MSAs) and 23 C-fiber (10 MIAs and 13 MSAs) nociceptors in hairy skin of pentobarbital sodium-anesthetized monkeys. An electrocutaneous search technique was used to locate the putative receptive fields of the MIAs. The response to mechanical and heat stimuli was determined before and after intradermal injection of a standard mixture of algesic/inflammatory mediators (bradykinin, histamine, serotonin, and prostaglandin E1). 3. All 25 MSAs, but only 65% of the MIAs, responded to the chemical stimulus. The A delta-fibers, both MSAs and responsive MIAs, and the responsive C-fiber MIAs gave a robust discharge. In contrast, the C-fiber MSAs (the conventional polymodal C-fiber nociceptors) exhibited a significantly weaker response. Three MIAs responded only to the chemical mixture and not to mechanical or heat stimuli. 4. Before injection of the chemical mixture, a significantly smaller proportion of C-fiber MIAs (50%) than of C-fiber MSAs (92%) responded to heat stimuli, whereas a similar proportion (38%) of A delta-fiber MIAs and MSAs were heat sensitive. 5. Approximately one-half of the MIAs and MSAs were sensitized to mechanical stimuli after the chemical injection, as manifest by a decreased threshold and/or an enlarged receptive field. 6. The chemical injection sensitized 90% of A delta-fiber MSAs, but only 8% of A delta-fiber MIAs, to heat stimuli. In contrast, 38% of C-fibers were sensitized. 7. In 14 fibers, the chemical stimulus resulted in sensitization to mechanical stimuli without sensitization to heat stimuli, or vice versa. This dissociated sensitized state suggests that the molecular mechanisms of sensitization to heat and mechanical stimuli differ. 8. In conclusion, a large proportion of primate cutaneous nociceptors respond to intradermal injection of algesic/inflammatory mediators and may also become sensitized to mechanical and/or heat stimuli.
A laser thermal stimulator system is described which enables the psychophysical and neurophysiological study of cutaneous thermal and pain sensations by means of a non-contact, precise stimulator. A carbon dioxide laser is used as the heat source with closed loop control of skin temperature via a sophisticated radiometer. Temperature steps of 0.1°C to 25°C have been achieved with rise rates of greater than 30°C/second. The temperature can be maintained to better than ±0.1°C over pulse durations of 0.3 seconds to 20 seconds.
Peripheral neural correlates of behavior in monkey and human related to sensory-discriminative aspects of pain
- R Price
- D D Beitel
- R E Hu
- J W Anderson
- D J Matthews
DUBNER, R., PRICE, D. D., BEITEL, R. E. & Hu, J. W. (1977).
Peripheral neural correlates of behavior in monkey and human
related to sensory-discriminative aspects of pain. In Pain in the
Trigeminal Region, ed. ANDERSON, D. J. & MATTHEWS, B.,
pp. 57-66. Elsevier, Amsterdam.
Primary afferent and spinal sensory neurons that respond to brief pulses of intense infrared laser radiation
- M Carmon
- A Frostig
DEVOR, M., CARMON, A. & FROSTIG, R. (1982). Primary afferent and
spinal sensory neurons that respond to brief pulses of intense
infrared laser radiation. Experimental Neurology 76,483-494.
A-fibre nociceptors with a fast response to heat are absent in monkey glabrous skin
- R D Meyer
- R A Campbell
TREEDE, R. D., MEYER, R. A. & CAMPBELL, J. N. (1991). A-fibre
nociceptors with a fast response to heat are absent in monkey
glabrous skin. Society for Neuroscience Abstracts 17, 293.
Similarity of threshold temperatures for first pain sensation, laser-evoked potentials and nociceptor activation
- R D Meyer
- R A Lesser
TREEDE, R. D., MEYER, R. A. & LESSER, R. P. (1994). Similarity of
threshold temperatures for first pain sensation, laser-evoked
potentials and nociceptor activation. In Proceedings of the 7th
World Congress on Pain, ed. GEBHART, G. F., HAMMOND, D. L. &
JENSEN, T. S., pp. 857-865. IASP Press, Seattle, WA, USA.
Statistical Software Manual
- W J Brown
- M B Engelmann
- L Hill
- M A Jennrich
DIXON, W. J., BROWN, M. B., ENGELMANN, L., HILL, M. A. &
JENNRICH, R. I. (1988). Statistical Software Manual. University of
California Press, Berkeley, CA, USA.
Correlation of capsaicin-induced changes in pain rating with laser evoked potential amplitude
- A Beydoun
- T J Morrow
- K L Casey
BEYDOUN, A., MORROW, T. J. & CASEY, K. L. (1991). Correlation of
capsaicin-induced changes in pain rating with laser evoked
potential amplitude. Society for Neuroscience Abstracts 17, 293.