No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
A search for activation of C nociceptors by sympathetic fibers in complex regional pain syndrome
Abstract
Although the term 'reflex sympathetic dystrophy' has been replaced by 'complex regional pain syndrome' (CRPS) type I, there remains a widespread presumption that the sympathetic nervous system is actively involved in mediating chronic neuropathic pain ["sympathetically maintained pain" (SMP)], even in the absence of detectable neuropathophysiology.
We have used microneurography to evaluate possible electrophysiological interactions in 24 patients diagnosed with CRPS I (n=13), or CRPS II (n=11) by simultaneously recording from single identified sympathetic efferent fibers and C nociceptors, while provoking sympathetic neural discharges in cutaneous nerves.
We assessed potential effects of sympathetic activity upon 35 polymodal nociceptors and 19 mechano-insensitive nociceptors, recorded in CRPS I (26 nociceptors) and CRPS II patients (28 nociceptors). No evidence of activation of nociceptors related to sympathetic discharge was found, although nociceptors in six CRPS II patients exhibited unrelated spontaneous pathological nerve impulse activity.
We conclude that activation of nociceptors by sympathetic efferent discharges is not a cardinal pathogenic event in either CRPS I or CRPS II patients.
This study shows that sympathetic-nociceptor interactions, if they exist in patients communicating chronic neuropathic pain, must be the exception.
... 2,3 los diferentes mecanismos involucrados en las distintas sensaciones de dolor siguen siendo pobremente comprendidos, pero existe una amplia evidencia acerca de que las descargas anormales de las neuronas somatosensoriales enfermas serían las responsables. 1,9,10,16,26,27 la actividad espontánea en el sistema nociceptivo periférico también puede provocar cambios en el sistema nervioso central responsables de la hiperalgesia y alodinia. 21,43 Por lo tanto, los fármacos dirigidos a controlar los mecanismos generadores de descargas espontáneas de los nociceptores potencialmente podrían ofrecer un excelente tratamiento para el dolor neuropático. ...
... 19 Papel funcional de la actividad espontánea de los nociceptores C y sus implicancias para las pruebas de drogas este estudio ha confirmado, con la evidencia previa microneurográfica, que los nociceptores de tipo C generalmente son más activos en los pacientes con dolor neuropático que en los sujetos sanos. 9,26,28,35 Puesto que la estimulación selectiva intraneural de los nociceptores C evoca una percepción de ardor o dolor profundo en los sujetos control, 24 es razonable asumir que la actividad espontánea en los pacientes con dolor neuropático contribuye a su dolor espontáneo (a condición de que se satisfagan ciertos requisitos temporales y espaciales sumatorios). De esto se deduce que la detección y cuantificación de la actividad espontánea de los nociceptores C pueden proporcionar una medida objetiva útil de la fuente de las sensaciones dolorosas. ...
Los nociceptores de las fibras de tipo C normalmente no disparan potenciales de acción a menos que sean estimulados por estímulos nocivos adecuados. Sin embargo, en estados patológicos, los nociceptores pueden volverse hiperexcitables y generan descargas ectópicas espontáneas. El objetivo de este estudio fue comparar modelos de dolor neuropático en ratas y evaluar su idoneidad para modelar la actividad espontánea de los nociceptores C que se encontró en pacientes con dolor neuropático. Los estudios fueron realizados en ratas normales (n=40), sujetos humanos sanos (n=15), pacientes con dolor neuropático periférico (n=20) y en cinco modelos de dolor neuropático en ratas: aplastamiento de nervio (n=24), sutura (n=14), lesión por compresión crónica (n = 12), neuropatía diabética inducida por estreptozotocina [STZ] (n=56) y neuropatía inducida por 2,3-dideoxicitidina [ddC] (n=15). Los registros microneurográficos fueron combinados con la estimulación eléctrica para monitorear la actividad en múltiples fibras de tipo C. La estimulación con 0,25 Hz permitió que los impulsos espontáneos puedan ser identificados por las fluctuaciones de la latencia basal. Las fluctuaciones anormales de la latencia podrían ser producidas por varios mecanismos. La actividad espontánea fue identificada de manera más fidedigna por la presencia de incrementos inexplicables de la latencia, correspondientes a dos o más potenciales de acción adicionales. La actividad espontánea estuvo presente en determinada proporción de nociceptores de tipo C insensibles a los estímulos mecánicos en los pacientes y en todos los modelos en ratas. Los tres modelos animales de lesión traumática focal en nervios presentaron la proporción más alta (59,5%), mientras que los dos modelos de polineuropatía tuvieron menos (18,6%), en tanto que los pacientes mostraron una proporción intermedia (33,3%). No se registraron nociceptores C sensibles a los estímulos mecánicos espontáneamente activos. Los registros microneurográficos de la actividad espontánea de los nociceptores C enfermos pueden ser de utilidad para el estudio de drogas a corto y largo plazo, tanto en animales como en humanos.
... To clarify the link between multiple spiking and neuropathic pain, we investigated single nociceptors in neuropathy patients with and without pain for the occurrence of unidirectional block patterns and for spontaneous activity. Spontaneous activity in nociceptors can be used as a characteristic marker for ongoing pain [3,18]. We therefore analysed whether multiple spiking occurred more often in spontaneously active nociceptors. ...
... In the present study, we report an association between the occurrence of multiple spiking to single electrical stimulation and spontaneous activity in C nociceptors of patients with painful neuropathy. Spontaneous activity in C nociceptors has been suggested to be a major contributor to chronic pain in neuropathic pain conditions [3,18]. However, earlier microneurography studies in diabetic neuropathy patients also revealed consequences of neuropathy that are not linked to pain, such as a loss of mechanosensitive nociceptors leading to neuropathy-induced desensitization [19]. ...
Multiple firing of C nociceptors upon a single electrical stimulus has been suggested to be a possible mechanism contributing to neuropathic pain. Because this phenomenon maybe based on a unidirectional conduction block, it might also be related to neuropathic changes without a direct link to pain. We investigated painful neuropathy patients using microneurography and analysed nociceptors for the occurrence of multiple spiking and spontaneous activity. In 11 of 105 nociceptors, double spiking was found, with 1 fibre even showing triple spikes on electrical stimulation. The interval between the main action potential and the multiple spikes ranged from 13 to 100 ms. There was a significant association between spontaneous activity and multiple spiking in C nociceptors, with spontaneous activity being present in 9 of 11 fibres with multiple spiking, but only in 21 of 94 nociceptors without multiple spiking (P<.005, Fisher exact test). Among the 75 C nociceptors without spontaneous activity, only 2 nociceptors showed multiple spiking. In 8 neuropathy patients without pain, double spiking was found only in 4 of 90 nociceptors. Multiple spiking of nociceptors coincides with spontaneous activity in nociceptors of painful neuropathy patients. We therefore conclude that rather than being a generic sign of neuropathy, multiple spiking is linked to axonal hyperexcitability and spontaneous activity of nociceptors. It is still unclear whether it also is mechanistically related to the clinical pain level.
... Using microneurography to evaluate possible electrophysiological interactions by simultaneously recording single identified sympathetic efferent fibers and C nociceptors while provoking sympathetic neuronal discharges in cutaneous nerves, Campero et al. assessed potential effects of sympathetic activity upon 35 polymodal nociceptors and 19 mechano-insensitive nociceptors in patients with CRPS I and II. These studies failed to reveal activation of nociceptors related to sympathetic discharge, thereby suggesting that sympathetic-nociceptor interactions are the exception [59]. ...
The utilization and methodology of functional Infrared Imaging in evaluation patients with presumptive CRPS.
... In peripheral sensory neurons, this type of activity is rarely found in healthy individuals 1,2 . Instead, it is prevalent in many people with chronic neuropathic [3][4][5] and musculoskeletal 6,7 conditions, with a report indicating that the levels of spontaneous activity can directly correlate with levels of pain 8 . Consistent with these observations in humans, an increase in the proportion of sensory neurons with spontaneous activity has also been reported in rodent models of chronic pain 3,[9][10][11] . ...
Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) via in vivo imaging in a mouse model of pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used this data to train a machine leaning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in two different models of pain: intraplantar Complete Freund's Adjuvant and antigen-induced arthritis, with accuracies of 90.0% +/-1.2 and 85.9 % +/-2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different lab using a different microscope configuration (Accuracy = 94.0 % +/2.2). We provide a Google Colaboratory Notebook to allow anyone easy access to this novel tool, for assessment of peripheral neuron activity in their own calcium imaging setups.
... In peripheral sensory neurons, this type of activity is rarely found in healthy individuals 1,2 . Instead, it is prevalent in many people with chronic neuropathic [3][4][5] and musculoskeletal 6,7 conditions, with a report indicating that the levels of spontaneous activity can directly correlate with levels of pain 8 . Consistent with these observations in humans, an increase in the proportion of sensory neurons with spontaneous activity has also been reported in rodent models of chronic pain 3,[9][10][11] . ...
Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) via in vivo imaging in a mouse model of pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used this data to train a machine leaning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in two different models of pain: intraplantar Complete Freund's Adjuvant and antigen-induced arthritis, with accuracies of 90.0% +/- 1.2 and 85.9 % +/-2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different lab using a different microscope configuration (Accuracy = 94.0 % +/2.2). We provide a Google Colaboratory Notebook to allow anyone easy access to this novel tool, for assessment of peripheral neuron activity in their own calcium imaging setups.
... 4 Microneurographic recordings in patients with neuropathic pain have shown spontaneous firing of c nociceptors, which are associated with ongoing pain and hyperalgesia. 7,37,38 Capsaicin administration can improve pain management in this group of patients for whom pain is maintained by hyperactive nociceptors. ...
Capsaicin is a specific agonist of transient receptor potential vanilloid 1 (TRPV1), which is enriched in nociceptors. Capsaicin not only produces acute pain but also leads to long-lasting analgesia in patients with chronic pain. Although capsaicin-induced TRPV1 and Ca2+/calpain-dependent ablation of axonal terminals is necessary for long-lasting analgesia, the mechanisms underlying capsaicin-induced ablation of axonal terminals and its association with analgesia are not fully understood. Microtubules are composed of tubulin polymers and serve as a main axonal cytoskeleton maintaining axonal integrity. In this study, we hypothesized that capsaicin would increase the depolymerization of microtubules and lead to axonal ablation and analgesia for trigeminal neuropathic pain. Paclitaxel, a microtubule stabilizer, decreased capsaicin-induced ablation of axonal terminals in time-lapsed imaging in vitro. Capsaicin increases free tubulin in dissociated sensory neurons, which was inhibited by paclitaxel. Consistently, subcutaneous injection of paclitaxel prevented capsaicin-induced axonal ablation in hindpaw skin. Capsaicin administration to facial skin produced analgesia for mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve, which was prevented by the co-administration of paclitaxel and capsaicin. Whole-mount staining of facial skin showed that paclitaxel reduced capsaicin-induced ablation of peptidergic afferent terminals. Despite the suggested involvement of TRPV1 Ser801 phosphorylation on microtubule integrity, capsaicin-induced analgesia was not affected in TRPV1 S801A knock-in mice. In conclusion, capsaicin-induced depolymerization of axonal microtubules determined capsaicin-induced ablation of nociceptive terminals and the extent of analgesia. Further understanding of TRPV1/Ca2+-dependent mechanisms of capsaicin-induced ablation and analgesia may help to improve the management of chronic pain.
... Compression block of conduction selectively in Aβ fibers reduced allodynia without reducing spontaneous pain in patients with chronic peripheral neuralgia, implicating separate roles for activity in A-fibers and C-fibers during chronic pain (Koltzenburg et al., 1994). Ongoing chronic pain was closely associated with C-fiber hyperactivity in patients suffering from various kinds of peripheral neuropathy (e.g., diabetic) (Kleggetveit et al., 2012;Ochoa & Torebjörk, 1989;Ochoa et al., 2005), complex regional pain syndrome (Campero et al., 2010), and fibromyalgia (Serra et al., 2014). The most prominent correlate of chronic pain has been spontaneous activity, especially in "mechanically insensitive" or "silent" C-fiber nociceptors that only become mechanically sensitive following sufficient noxious stimulation (Schmidt et al., 2000). ...
Chronic pain lasting months or longer is very common, poorly treated, and sometimes devastating. Nociceptors are sensory neurons that usually are silent unless activated by tissue damage or inflammation. In humans their peripheral activation evokes conscious pain, and their spontaneous activity is highly correlated with spontaneous pain. Persistently hyperactive nociceptors mediate increased responses to normally painful stimuli (hyperalgesia) in chronic conditions and promote the sensitization of central pain pathways that allows low-threshold mechanoreceptors to elicit painful responses to innocuous stimuli (allodynia). Investigations of rodent models of neuropathic pain and hyperalgesic priming have revealed many alterations in nociceptors and associated cells that are implicated in the development and maintenance of chronic pain. These include chronic nociceptor hyperexcitability and spontaneous activity, sprouting, synaptic plasticity, changes in intracellular signaling, and modified responses to opioids, along with alterations in the expression and translation of thousands of genes in nociceptors and closely linked cells.
... 67 However, a larger study that used microneurography did not find such evidence in patients with CRPS-I or CRPS-II. 28 Sympathetic sensory coupling at the injury site has been tested in patients with postamputation stump pain. Perineuronal injection of epinephrine close to a peripheral nerve neuroma produced intense pain. ...
... In humans single fibre recordings with microneurograpy have not only revealed that neuronal and axonal hyper-excitability are linked to sensory symptoms such as pain or paresthesia in patients Burchiel and Baumann, 2004;Campero et al., 2010;Campero et al., 1998;Cline et al., 1989;Jorum et al., 2007;Mackel et al., 1994;Nordin et al., 1984;Nystrom and Hagbarth, 1981;Ochoa et al., 2005;Orstavik et al., 2006;Orstavik et al., 2003;Serra et al., 2009), but have also identified a higher incidence of spontaneous activity in C-nociceptors in patients with painful neuropathy as compared to non-painful neuropathy (Kleggetveit et al., 2012), indicating a causal role of this nociceptive input for ongoing clinical pain. The backtranslation of these clinical results into experimental models is problematic as mainly evoked pain behaviour (Serra, 2010) is assessed in animal models rather than spontaneous pain behaviour which more clinically relevant (Mogil, 2009). ...
The main underlying mechanisms of chronic pain are still unclear. In this thesis, two new approaches targeting the excitability of peripheral nociceptive neurons were employed to examine processes leading to ongoing nociceptive discharge. Thereby we aimed to contribute to the understanding of peripherally driven spontaneous pain that leads to suffering in many patients with chronic pain. We used a new model of low extracellular potassium application that induces ongoing nociceptor activity at the sensory endings of skin nociceptors and a slow depolarizing ramp stimulus that preferentially activates C-fibres and is more closely related to the physiologic induction of action potentials in primary afferent neurons. Low potassium solution unexpectedly led to a rapid and transient depolarisation that is probably mediated by a loss of ion selectivity in 2 pore domain potassium channels. However, the dominant effect of low potassium was a massive increase of intracellular sodium mediated primarily by an influx of sodium ions via NaV1.9 channels. Moreover, primary afferents lacking NaV1.9 such as cold sensitive A-fibres of the cornea did not increase their discharge upon stimulation with low potassium. Slow depolarizing ramp stimuli (4 Hz sinusoidal) were found to be more effective at activating C-fibres during cooling whereas traditional rectangular stimulation became less effective. This differential effect could be explained by cold-induced closure of two pore domain potassium channels leading to increased membrane resistance. The increased membrane resistance increases the membrane time constant whereby the same transmembrane current will more effectively change membrane potential. This mechanism has major clinical importance for cold-induced pain. The voltage-sensitive sodium channel NaV1.7 would have the ideal characteristics to mediate the activation upon slow depolarizing ramps as it is known to amplify such stimuli via a “ramp current”. Activation of C-fibres by sinusoidal stimuli was not blocked by TTX suggesting that NaV1.7 is not the only NaV that can respond to slow depolarizing changes in membrane potential. Innovative excitability tests were used to investigate peripheral nerve fibres of rats that had received cisplatin to induce an acute nephropathy and potentially a peripheral neuropathy. In treated animals, unmyelinated fibres were found to be more sensitive to slow depolarizing stimuli suggesting hyper-excitability. However, the number of animals was low and it remains unclear how robust this effect is. In summary, the model of potassium free extracellular solution was used to identify NaV1.9 and 2 pore domain potassium channels as major determinants of small fibre excitability that have already been linked to clinical chronic pain states. Moreover, the cold-induced hyper-excitability of unmyelinated fibres in response to slow depolarizing ramp stimuli found in our study has important mechanistic implications for the generation of cold-induced pain and hypersensitivity in patients with neuropathic pain. It will be of major interest to use the newly developed tests for axonal excitability in pathophysiologic conditions and ultimately in human tissue in order to specify promising molecular targets that can lead to innovative analgesic treatment options in the future.
... Similarly, conflicting sensory (visual) stimuli, such as the Necker cube, increased pain in conjunction with abnormal autonomic activity (asymmetric vasomotor responses) in CRPS patients [22]. However, electrophysiological investigation of the interaction between 54 nociceptive afferent and sympathetic efferent fibers with microneurography failed to show a direct link in 11 patients with CRPS type II or 13 patients with CRPS type I [16]. Therefore, indirect mechanisms of arousal-pain interaction (e.g., an increase in muscle tone that activates deep somatic sensitized afferents [103]) must be also considered. ...
Purpose
Although autonomic features are part of the diagnostic criteria for complex regional pain syndrome (CRPS), the role of the autonomic nervous system in CRPS pathophysiology has been downplayed in recent years. The purpose of this review is to redress this imbalance.
Methods
We focus in this review on the contribution of the autonomic nervous system to CRPS pathophysiology. In particular, we discuss regional sympathetic and systemic autonomic disturbances in CRPS and the mechanisms which may underlie them, and consider links between these mechanisms, immune disturbances and pain.
Results
The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS.
Conclusions
We conclude that alterations in the sympathetic nervous system contribute to CRPS pathology. Understanding these alterations may be an important step towards providing appropriate treatments for CRPS.
... Injection of the adrenomedullary stress hormone, epinephrine (functionally and chemically closely related to NE) near a neuroma was reported to produce intense pain (Chabal et al., 1992). However, in patients with painful polyneuropathy no evidence for sensitization to cutaneous iontophoresis of NE was found (Schattschneider et al., 2006), nor was evidence found for peripheral activation of C-fiber nociceptors by sympathetic activity in patients with CRPS (Campero et al., 2010)-in contrast to a report of sympathetic and noradrenergic activation of C fibers in a single patient with sympathetically maintained pain (Jorum et al., 2007). Thus, the conditions in which sympathetic activity excites primary sensory neurons in humans are not well understood. ...
Autonomic dysreflexia (AD) and neuropathic pain occur after severe injury to higher levels of the spinal cord. Mechanisms underlying these problems have rarely been integrated in proposed models of spinal cord injury (SCI). Several parallels suggest significant overlap of these mechanisms, although the relationships between sympathetic function (dysregulated in AD) and nociceptive function (dysregulated in neuropathic pain) are complex. One general mechanism likely to be shared is central sensitization – enhanced responsiveness and synaptic reorganization of spinal circuits that mediate sympathetic reflexes or that process and relay pain-related information to the brain. Another is enhanced sensory input to spinal circuits caused by extensive alterations in primary sensory neurons. Both AD and SCI-induced neuropathic pain are associated with spinal sprouting of peptidergic nociceptors that might increase synaptic input to the circuits involved in AD and SCI pain. In addition, numerous nociceptors become hyperexcitable, hypersensitive to chemicals associated with injury and inflammation, and spontaneously active, greatly amplifying sensory input to sensitized spinal circuits. As discussed with the aid of a preliminary functional model, these effects are likely to have mutually reinforcing relationships with each other, and with consequences of SCI-induced interruption of descending excitatory and inhibitory influences on spinal circuits, with SCI-induced inflammation in the spinal cord and in DRGs, and with activity in sympathetic fibers within DRGs that promotes local inflammation and spontaneous activity in sensory neurons. This model suggests that interventions selectively targeting hyperactivity in C-nociceptors might be useful for treating chronic pain and AD after high SCI.
... Using microneurography to evaluate possible electrophysiological interactions by simultaneously recording single identified sympathetic efferent fibers and C nociceptors while provoking sympathetic neuronal discharges in cutaneous nerves, Campero et al. assessed potential effects of sympathetic activity upon 35 polymodal nociceptors and 19 mechano-insensitive nociceptors in patients with CRPS I and II. These studies failed to reveal activation of nociceptors related to sympathetic discharge, thereby suggesting that sympathetic-nociceptor interactions are the exception [59]. ...
... Despite evidence showing the involvement of SNS in the pathophysiology of CRPS, the direct link between SNS activity and nociception remains to be delineated in CRPS patients: for example, in a study examining 24 CRPS patients and using microneurography techniques, no links were found between efferent fiber sympathetic activity and afferent activity in nociceptors innervating the symptomatic areas. 25 These findings might suggest that indirect mechanisms could be responsible for both the activation and the sensitization of nociceptors, not a direct coupling. One such mechanism could be due to a notable symptom of CRPS, vasoconstriction, which could influence nociceptor microenvironment or activate macrophages, which in turn would result in inflammatory mediator release. ...
Despite the severe pain and disability associated with complex regional pain syndrome (CRPS), the lack of understanding of the pathophysiological mechanisms supporting this enigmatic condition prevents the rational design of new therapies, a situation that is frustrating to both the physician and the patient. The review highlights some of the mechanisms thought to be involved in the pathophysiology of CRPS in preclinical models and CRPS patients, with the ultimate goal that understanding these mechanisms will lead to the design of efficacious, mechanism-based treatments available to the clinic.
... Inflammatory response was considered as one of the underlying contributors to the development and maintenance of CRPS, whereas the pharmacologic evidence using anti-inflammatory therapies on pro-inflammatory mediators was limited due to the trial quality, sample size and inconsistent reporting on the results [3]. Besides, the enhanced autonomic sympathetic activity was found facilitating nociceptive fibers to develop CRPS, but no direct evidence of activation of nociceptors related to sympathetic discharge was found [4]. Therefore, central nerve system (CNS) was concentrated on for its involvement in the pathogenesis of CRPS, especially when nerve injury existed [2,5]. ...
DRG is of importance in relaying painful stimulation to the higher pain centers and therefore could be a crucial target for early intervention aimed at suppressing primary afferent stimulation. Complex regional pain syndrome (CRPS) is a common pain condition with an unknown etiology. Recently added new information enriches our understanding of CRPS pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, and mechanisms of pain modulation, central sensitization, and autonomic functions in CRPS revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of CRPS. Epigenetics refers to mitotically and meiotically heritable changes in gene expression that do not affect the DNA sequence. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism , neurotransmitter responsiveness, and analgesic sensitivity, they are likely key factors in the development of chronic pain. In this dyad review series, we systematically examine the nerve injury-related changes in the neurological system and their contribution to CRPS. In this part, we first reviewed and summarized the role of neural sensitization in DRG neurons in performing function in the context of pain processing. Particular emphasis is placed on the cellular and molecular changes after nerve injury as well as different models of in-flammatory and neuropathic pain. These were considered as the potential molecular bases that underlie nerve injury-associated pathogenesis of CRPS.
... Nociceptors exhibited unrelated spontaneous pathological nerve impulse activity in the majority of CRPS patients. Therefore, no evidence of activation of nociceptors related to sympathetic discharge was found supporting the conclusion that nociceptor activation by sympathetic efferent discharges is not a cardinal pathogenic event in CRPS (Campero et al., 2010). Fig. 3. Stimulus-induced effects on MSNA in a control and phobic syncope patients. ...
Microneurography is a unique neurophysiological technique allowing direct recording of unmyelinated postganglionic sympathetic or afferent nociceptive fibers by tungsten needles inserted into a peripheral nerve fascicle. In recent years, microneurography has been used to ascertain autonomic impairments in central neurological disorders such as sleep disorders, Parkinson’s disease, amyotrophic lateral sclerosis, or vasovagal syncope. Abnormal resting muscle sympathetic nerve activity (MSNA) and skin sympathetic nerve activity (SSNA) or the abnormal sympathetic response to arousal have been described in these disorders, thereby clarifying important pathophysiological aspects of the underlying impairment.
... 51 This process results in peripheral sensitization, which subsequently enhances nociception and results in hypersensitivity to pain. 52 Micrography recordings have demonstrated spontaneous pathological nerve impulse activity in nociceptive neurons in some patients with CRPS, 53 supporting the idea that peripheral sensitization is involved in CRPS. 166 peripheral and central mechanisms (yellow boxes) lead to a multitude of different typical signs and symptoms (pink), which can guide selection of mechanism-based treatment options (blue). ...
Complex regional pain syndromes (CRPS) are multifactorial disorders with complex aetiology and pathogenesis. Management of CRPS is challenging, partly because of a lack of clinical data regarding the efficacy of the various therapies, and partly because successful treatment of CRPS requires a multidisciplinary, patient-tailored approach. The pain in CRPS is often described as typical 'burning' neuropathic pain, and is accompanied by a variety of sensory, motor and autonomic signs and symptoms. Because research into therapies specifically in CRPS has been scarce, treatment for these syndromes has been largely based on therapeutic strategies adapted from neuropathic pain states; however, increased understanding of the pathogenesis of CRPS has provided the opportunity to develop mechanism-based treatments. The interactions between the multiple pathophysiological mechanisms that contribute to the development, progression and maintenance of CRPS remain poorly understood. This Review describes the challenges in linking the current theories and knowledge of pathophysiological mechanisms to the mode of actions of the different treatment approaches. We discuss the current treatment strategies for CRPS, including pharmacotherapy, sympathetic ganglion block interventions, psychological support, physiotherapy and occupational therapy, and establish the concept of mechanism-based treatment for CRPS.
... Inflammatory response was considered as one of the underlying contributors to the development and maintenance of CRPS, whereas the pharmacologic evidence using anti-inflammatory therapies on pro-inflammatory mediators was limited due to the trial quality, sample size and inconsistent reporting on the results [3]. Besides, the enhanced autonomic sympathetic activity was found facilitating nociceptive fibers to develop CRPS, but no direct evidence of activation of nociceptors related to sympathetic discharge was found [4]. Therefore, central nerve system (CNS) was concentrated on for its involvement in the pathogenesis of CRPS, especially when nerve injury existed [2,5]. ...
Abstract DRG is of importance in relaying painful stimulation to the higher pain centers and therefore could be a crucial target for early intervention aimed at suppressing primary afferent stimulation. Complex regional pain syndrome (CRPS) is a common pain condition with an unknown etiology. Recently added new information enriches our understanding of CRPS pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, and mechanisms of pain modulation, central sensitization, and autonomic functions in CRPS revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of CRPS. Epigenetics refers to mitotically and meiotically heritable changes in gene expression that do not affect the DNA sequence. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, neurotransmitter responsiveness, and analgesic sensitivity, they are likely key factors in the development of chronic pain. In this dyad review series, we systematically examine the nerve injury-related changes in the neurological system and their contribution to CRPS. In this part, we first reviewed and summarized the role of neural sensitization in DRG neurons in performing function in the context of pain processing. Particular emphasis is placed on the cellular and molecular changes after nerve injury as well as different models of inflammatory and neuropathic pain. These were considered as the potential molecular bases that underlie nerve injury-associated pathogenesis of CRPS.
... The role of surgical interventions for trigeminal neuropathies remains unclear due to a lack of good evidence with prospective controlled trials. Sympathetic blockade and sympathetic radio frequency remain unproven, and their use may be ineffectual due to recent findings showing a lack of activation of nociceptors related to sympathetic discharge in chronic neuropathic pain patients [73]. Other proposed surgical interventions include using a gamma knife that targets the sphenopalatine ganglion and brain stimulation. ...
SUMMARY Trigeminal neuropathic pains have presented diagnostic and therapeutic challenges to providers. In addition, knowledge of pathophysiology, current classification systems, taxonomy and phenotyping of these conditions are incomplete. While trigeminal neuralgia is the most identifiable and studied, other conditions are being recognized and require distinct management approaches. Furthermore, other facial pain conditions such as atypical odontalgia and burning mouth syndrome are now considered to have neuropathic elements in their etiology. This article reviews current knowledge on the pathophysiology, diagnosis and management of neuropathic pain conditions involving the trigeminal nerve, to include: trigeminal neuralgia, trigeminal neuropathic pain (with traumatically induced neuralgia and atypical odontalgia) and burning mouth syndrome. Treatment modalities are reviewed based on current and best available evidence. Trigeminal neuralgia is managed with anticonvulsant drugs as the first line, with surgical options providing variable results. Trigeminal neuropathic pain is managed medically based on the guidelines for other neuropathic pain conditions. Burning mouth syndrome is also treated with a number of neuropathic medications, both topical and systemic. In all these conditions, patients need to be thoroughly educated about their condition, involved in its management, and be provided with supportive and adjunctive treatment resources.
... To differentiate between ephaptic interactions between sympathetic efferents and nociceptive afferents or catecholamine-induced activation of nociceptive nerve endings, single fibre recording was performed in CRPS patients and a patient with SMP. The results showed that endogenously released catecholamines, but not ephaptic interactions mediated SMP (Jorum et al., 2007;Campero et al., 2010). Even in an animal model of chronic neuroma, no ephaptic transmission between postganglionic and afferent fibres existed (Blumberg and Janig, 1982). ...
Acute Complex regional Pain Syndrome (CRPS) is associated with signs of inflammation such as increased skin temperature, edema, skin colour changes and pain. Pro-inflammatory cytokines (tumor necrosis factor- α (TNF-α), interleukin-2 (IL-2), IL-1beta, IL-6) are up-regulated, whereas anti-inflammatory cytokines (IL-4, IL-10) are diminished. Adaptive immunity seems to be involved in CRPS pathophysiology as many patients have autoantibodies directed against β2 adrenergic and muscarinic-2 receptors. In an animal tibial fracture model changes in the innate immune response such as up-regulation of keratinocytes are also found. Additionally, CRPS is accompanied by increased neurogenic inflammation which depends mainly on neuropeptides such as CGRP and Substance P.
Besides inflammatory signs, sympathetic nervous system involvement in CRPS results in cool skin, increased sweating and sympathetically-maintained pain. The norepinephrine level is lower in the CRPS-affected than contralateral limb, but sympathetic sprouting and up-regulation of alpha-adrenoceptors may result in an adrenergic supersensitivity.
The sympathetic nervous system and inflammation interact: norepinephrine influences the immune system and the production of cytokines. There is substantial evidence that this interaction contributes to the pathophysiology and clinical presentation of CRPS, but this interaction is not straightforward. How inflammation in CRPS might be exaggerated by sympathetic transmitters requires further elucidation.
... NP patients complain of spontaneous pains, described as burning, deep aching, or dysesthetic [2] [3]. The different mechanisms involved in different pain sensations are still poorly understood, but there is ample evidence that abnormal discharges from diseased somatosensory neurons are responsible [1] [9] [10] [16] [26] [27]. Spontaneous activity in the peripheral nociceptor system may also trigger central nervous system changes responsible for hyperalgesia and allodynia [21] [43]. ...
C-nociceptors do not normally fire action potentials unless challenged by adequate noxious stimuli. However, in pathological states nociceptors may become hyperexcitable and may generate spontaneous ectopic discharges. The aim of this study was to compare rat neuropathic pain models and to assess their suitability to model the spontaneous C-nociceptor activity found in neuropathic pain patients. Studies were performed in normal rats (n=40), healthy human subjects (n=15), peripheral neuropathic pain patients (n=20), and in five rat neuropathic pain models: nerve crush (n=24), suture (n=14), chronic constriction injury (n=12), STZ-induced diabetic neuropathy (n=56), and ddC-induced neuropathy (n=15). Microneurographic recordings were combined with electrical stimulation to monitor activity in multiple C fibers. Stimulation at 0.25 Hz allowed spontaneous impulses to be identified by fluctuations in baseline latency. Abnormal latency fluctuations could be produced by several mechanisms, and spontaneous activity was most reliably identified by the presence of unexplained latency increases corresponding to two or more additional action potentials. Spontaneous activity was present in a proportion of mechano-insensitive C-nociceptors in the patients and all rat models. The three focal traumatic nerve injury models provided the highest proportion (59.5%), whereas the two polyneuropathy models had fewer (18.6%), and the patients had an intermediate proportion (33.3%). Spontaneously active mechano-sensitive C-nociceptors were not recorded. Microneurographic recordings of spontaneous activity in diseased C-nociceptors may be useful for both short- and long-term drug studies, both in animals and in humans.
Heightened spontaneous activity in sensory neurons is often reported in individuals living with chronic pain. It is possible to study this activity in rodents using electrophysiology, but these experiments require great skill and can be prone to bias. Here, we have examined whether in vivo calcium imaging with GCaMP6s can be used as an alternative approach. We show that spontaneously active calcium transients can be visualised in the fourth lumbar dorsal root ganglion (L4 DRG) through in vivo imaging in a mouse model of inflammatory pain. Application of lidocaine to the nerve, between the inflamed site and the DRG, silenced spontaneous firing and revealed the true baseline level of calcium for spontaneously active neurons. We used these data to train a machine learning algorithm to predict when a neuron is spontaneously active. We show that our algorithm is accurate in 2 different models of pain: intraplantar complete Freund adjuvant and antigen-induced arthritis, with accuracies of 90.0% ±1.2 and 85.9% ±2.1, respectively, assessed against visual inspection by an experienced observer. The algorithm can also detect neuronal activity in imaging experiments generated in a different laboratory using a different microscope configuration (accuracy = 94.0% ±2.2). We conclude that in vivo calcium imaging can be used to assess spontaneous activity in sensory neurons and provide a Google Colaboratory Notebook to allow anyone easy access to our novel analysis tool, for the assessment of spontaneous neuronal activity in their own imaging setups.
Distal symmetric diabetic peripheral polyneuropathy (DPN) is the most common form of neuropathy in the world, affecting 30 to 50% of diabetic individuals and resulting in significant morbidity and socioeconomic costs. This review summarizes updates in the diagnosis and management of DPN. Recently updated clinical criteria facilitate bedside diagnosis, and a number of new technologies are being explored for diagnostic confirmation in specific settings and for use as surrogate measures in clinical trials. Evolving literature indicates that distinct but overlapping mechanisms underlie neuropathy in type 1 versus type 2 diabetes, and there is a growing focus on the role of metabolic factors in the development and progression of DPN. Exercise-based lifestyle interventions have shown therapeutic promise. A variety of potential disease-modifying and symptomatic therapies are in development. Innovations in clinical trial design include the incorporation of detailed pain phenotyping and biomarkers for central sensitization.
Many patients experience positive symptoms after traumatic nerve injury. Despite the increasing number of experimental studies in models of peripheral neuropathy and the knowledge acquired, most of these patients lack an effective treatment for their chronic pain. One possible explanation might be that most of the preclinical studies focused on the development of mechanical or thermal allodynia/hyperalgesia, neglecting that most of the patients with peripheral neuropathies complain mostly about spontaneous forms of pains. Here, we summarize the aberrant electrophysiological behavior of peripheral nerve fibers recorded in experimental models, the underlying pathophysiological mechanisms, and their relationship with the symptoms reported by patients. Upon nerve section, axotomized but also intact fibers develop ectopic spontaneous activity. Most interestingly, a proportion of axotomized fibers might present receptive fields in the skin far beyond the site of damage, indicative of a functional cross talk between neuromatose and intact fibers. All these features can be linked with some of the symptoms that neuropathic patients experience. Furthermore, we spotlight the consequence of primary afferents with different patterns of spontaneous discharge on the neural code and its relationship with chronic pain states. With this article, readers will be able to understand the pathophysiological mechanisms that might underlie some of the symptoms that experience neuropathic patients, with a special focus on spontaneous pain.
Nerve conduction studies (NCS) are an essential aspect of the assessment of patients with peripheral neuropathies. However, conventional NCS do not reflect activation of small afferent fibers, including Aδ and C fibers. A definitive gold standard for laboratory evaluation of these fibers is still needed and therefore, clinical evaluation remains fundamental in patients with small fiber neuropathies (SFN). Several clinical and research techniques have been developed for the assessment of small fiber function, such as (i) microneurography, (ii) laser evoked potentials, (iii) contact heat evoked potentials, (iv) pain-related electrically evoked potentials, (v) quantitative thermal sensory testing, (vi) skin biopsy-intraepidermal nerve fiber density and (vii) corneal confocal microscopy. The first five are physiological techniques, while the last two are morphological. They all have advantages and limitations, but the combined use of an appropriate selection of each of them would lead to gathering invaluable information for the diagnosis of SFN. In this review, we present an update on techniques available for the study of small afferent fibers and their clinical applicability. A summary of the anatomy and important physiological aspects of these pathways, and the clinical manifestations of their dysfunction is also included, in order to have a minimal common background.
Complex regional pain syndrome (CRPS) is a relatively rare, but debilitating condition that may occur after limb or peripheral nerve trauma. Typical symptoms of CRPS include swelling, allodynia, hyperalgesia, and skin temperature changes. Although a variety of pharmacological and non-pharmacological approaches are commonly used in caring for individuals with CRPS, they are frequently ineffective and often associated with side effects and/or additional risks. Previously, elastomeric orthotic garments have been shown to decrease neuropathic pain, reduce edema, and increase proprioception, but no previous reports have described their use in treating CRPS. Accordingly, this case series describes our experiences using a Lycra-based, custom-fabricated Dynamic Movement Orthosis (DMO) as a novel treatment to reduce the symptoms of CRPS and promote function. Four patients were included in this case series, all of whom had very different causes for their CRPS, including a combat-related gunshot injury resulting in multiple foot fractures with a partial nerve injury, a post-metatarsophalangeal fusion, an L5 radiculopathy, and a case of post-lower leg fasciotomies. These four patients all reported subjective improvement in their pain, function, and exercise tolerance in association with their DMO use. All patients demonstrated reduced use of analgesic medications. The pre- and post-DMO lower extremity functional scale showed clinically significant improvement in the two patients for which it was obtained.
To address the global burden of sickle cell disease (SCD) and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to: patient-reported outcomes (PROs), pain (non-PROs), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the PROs, pain, and brain panels, as well as relevant findings and recommendations from the biomarkers panel. The panels identify end points, where there were supporting data, to use in clinical trials of SCD. In addition, the panels discuss where further research is needed to support the development and validation of additional clinical trial end points.
This account of the condition now termed complex regional pain syndrome (CRPS) spans approximately 462 years since a description embodying similar clinical features was described by Ambroise Paré in 1557. While reviewing its historical origins, the text describes why it became necessary to change the taxonomies of two clinical syndromes with similar pathophysiologies to one which acknowledges this aspect but does not introduce any mechanistic overtones. Discussed at length is the role of the sympathetic component of the autonomic nervous system (ANS) and why its dysfunction has both directly and indirectly influenced our understanding of the inflammatory aspects of CRPS. As the following article will show, our knowledge has expanded in an exponential fashion to include musculoskeletal, immune, autoimmune, central and peripheral nervous system and ANS dysfunction, all of which increase the complexity of its clinical management. A burgeoning literature is beginning to shed light on the mechanistic aspects of these syndromes and the increasing evidence of a genetic influence on such factors as autoimmunity, and its importance is also discussed at length. An important aspect that has been missing from the diagnostic criteria is a measure of disease severity. The recent validation of a CRPS Severity Score is also included. © American Society of Regional Anesthesia & Pain Medicine 2019. No commercial re-use. See rights and permissions. Published by BMJ.
The technique of microneurography - recording neural traffic from nerves in awake humans - has provided us with unrivalled insights into afferent and efferent processes in the peripheral nervous system for over 50 years. We review the use of microneurography to study single C-fiber afferents and provide an overview of the knowledge gained, with views to future investigations. C-fibers have slowly-conducting, thin-diameter, unmyelinated axons, and make up the majority of the fibers in peripheral nerves (~80%). Using microneurography in humans, C-fiber afferents have been differentiated into discrete sub-classes that encode specific qualities of stimuli on the skin and their functional roles have been investigated. Afferent somatosensory information provided by C-fibers underpins various positive and negative affective sensations from the periphery, including: mechanical, thermal and chemical pain (C-nociceptors); temperature (C-thermoreceptors); and positive affective aspects of touch (C-tactile afferents). Insights from microneurographic investigations have revealed the complexity of the C-fiber system, methods for delineating fundamental C-fiber populations in a translational manner, how C-fiber firing can be used to identify nerve deficits in pathological states, and how the responses from C-fibers may be modified to change sensory percepts, including decreasing pain. Understanding these processes may lead to future medical interventions to diagnose and treat C-fiber dysfunction.
A variety of insults and mechanisms cause head and facial pain. Nociceptive pathways carrying the unpleasant physical and emotional perception of pain excite based on actual or impending tissue damage. Facial pain in particular possesses a large differential diagnosis that can be narrowed with historical facts pertinent to the patient. An understanding of the pathophysiology of facial pain will help the practitioner to the correct diagnosis and treatment for the patient. Causes of facial pain include acute insult, neurogenic, inflammatory, post-traumatic, and idiopathic.
Graded motor imagery (GMI) and mirror therapy (MT) is thought to improve pain in patients with complex regional pain syndrome (CRPS) types 1 and 2. However, the evidence is limited and analysis are not independent between types of CRPS. The purpose of this review was to analyze the effects of GMI and MT on pain in independent groups of patients with CRPS types 1 and 2. Searches for literature published between 1990 and 2016 were conducted in databases. Randomized controlled trials that compared GMI or MT with other treatments for CRPS types 1 and 2 were included. Six articles met the inclusion criteria and were classified from moderate to high quality. The total sample was composed of 171 participants with CRPS type 1. Three studies presented GMI with 3 components and three studies only used the MT. The studies were heterogeneous in terms of sample size and the disorders that triggered CRPS type 1. There were no trials that included participants with CRPS type 2. GMI and MT can improve pain in patients with CRPS type 1; however, there is not sufficient evidence to recommend these therapies over other treatments given the small size and heterogeneity of the studied population.
Skin abnormalities, such as discoloration, edema, temperature alterations and abnormal sweating, have led many to conclude that Complex Regional Pain Syndrome (CRPS), previously known as Reflex Sympathetic Dystrophy (RSD), is mediated by the sympathetic nervous system. These previous clinical observations led to the concept that disrupting sympathetic innervation to an affected extremity, by chemical blockade or surgical disruption of the sympathetic chain, could improve symptoms. However, recent evidence has raised questions about the primary role of the sympathetic nervous system in CRPS/RSD, and clinical results from disruption of sympathetic innervation in patients with CRPS/RSD have remained inconsistent.
Complex regional pain syndrome (CRPS) is the current consensus-derived name for a syndrome usually triggered by limb trauma. Required elements include prolonged, disproportionate distal-limb pain and microvascular dysregulation (e.g., edema or color changes) or altered sweating. CRPS-II (formerly "causalgia") describes patients with identified nerve injuries. CRPS-I (formerly "reflex sympathetic dystrophy") describes most patients who lack evidence of specific nerve injuries. Diagnosis is clinical and the pathophysiology involves combinations of small-fiber axonopathy, microvasculopathy, inflammation, and brain plasticity/sensitization. Females have much higher risk and workplace accidents are a well-recognized cause. Inflammation and dysimmunity, perhaps facilitated by injury to the blood-nerve barrier, may contribute. Most patients, particularly the young, recover gradually, but treatment can speed healing. Evidence of efficacy is strongest for rehabilitation therapies (e.g., graded-motor imagery), neuropathic pain medications, and electric stimulation of the spinal cord, injured nerve, or motor cortex. Investigational treatments include ketamine, botulinum toxin, immunoglobulins, and transcranial neuromodulation. Nonrecovering patients should be re-evaluated for neurosurgically treatable causal lesions (nerve entrapment, impingement, infections, or tumors) and treatable potentiating medical conditions, including polyneuropathy and circulatory insufficiency. Earlier impressions that CRPS represents malingering or psychosomatic illness have been replaced by evidence that CRPS is a rare complication of limb injury in biologically susceptible individuals.
DRG is of importance in relaying painful stimulation to the higher pain centers and therefore could be a crucial target for early intervention aimed at suppressing primary afferent stimulation. Complex regional pain syndrome (CRPS) is a common pain condition with an unknown etiology. Recently added new information enriches our understanding of CRPS pathophysiology. Researches on genetics, biogenic amines, neurotransmitters, and mechanisms of pain modulation, central sensitization, and autonomic functions in CRPS revealed various abnormalities indicating that multiple factors and mechanisms are involved in the pathogenesis of CRPS. Epigenetics refers to mitotically and meiotically heritable changes in gene expression that do not affect the DNA sequence. As epigenetic modifications potentially play an important role in inflammatory cytokine metabolism, neurotransmitter responsiveness, and analgesic sensitivity, they are likely key factors in the development of chronic pain. In this dyad review series, we systematically examine the nerve injury-related changes in the neurological system and their contribution to CRPS. In this part, we first reviewed and summarized the role of neural sensitization in DRG neurons in performing function in the context of pain processing. Particular emphasis is placed on the cellular and molecular changes after nerve injury as well as different models of inflammatory and neuropathic pain. These were considered as the potential molecular bases that underlie nerve injury-associated pathogenesis of CRPS.
Central pain can easily be described as hallucinatory pain, being couched as a disturbance of sensory information transfer along an uninhibited reverberating corticothalamocortical sensory channel. This generator alters the widely distributed small-world architecture of the brain, which can be neuroimaged, for instance, as an alteration of brain rhythms in multiple brain areas. These by themselves are not responsible for the sustenance of the pain but may contribute to the different qualities thereof. © 2012 Springer Science+Business Media, LLC. All rights reserved.
T-type calcium channels are a potential novel target for treatment of neuropathic pain such as painful diabetic neuropathy. ABT-639 is a peripherally acting, highly selective, T-type Cav3.2 calcium channel blocker that has demonstrated analgesic efficacy in preclinical models and may have the potential to reduce spontaneous fiber activity. Microneurography is a unique technique that directly assesses the function of peripheral sensory afferents and measures abnormal spontaneous activity in single peripheral nociceptive C-fibers. Abnormal spontaneous activity in C-nociceptors functions as a marker for spontaneous pain, as reduction of this activity could indicate analgesic efficacy. This randomized, double-blind, controlled study evaluated the effects of a single, 100-mg oral dose of ABT-639, compared with placebo, on abnormal spontaneous activity in peripheral C-nociceptors, measured for the first time by microneurography in adult patients with painful diabetic neuropathy. Lidocaine was included in this study and compared with placebo. Pharmacokinetics and safety of ABT-639 were evaluated. Thirty-nine patients were randomized and a total of 56 analyzable C-nociceptors with spontaneous activity were identified in 34 patients. There were no significant differences in C-nociceptor activities after ABT-639 treatment vs placebo. Similar findings were observed for lidocaine vs placebo. There were no clinically significant findings in the safety of ABT-639. Further research of T-type Cav3.2 calcium channels as potential treatment targets for painful diabetic neuropathy is warranted. The utilization of microneurography as a means to measure abnormal activity in C-nociceptors in human clinical studies opens new possibilities for future studies of compounds targeting peripheral nerve hyperexcitability. ClinicalTrials.gov identifier: NCT01589432.
Introduction: Complex regional pain syndrome (CRPS) is a disorder characterized by pain as well as a myriad of sensory, autonomic, and motor disturbances. We are reporting a case of child diagnosed with CRPS and successfully treated with supraclavicular brachial plexus catheter infusion of local anesthetic. Case Report: An eight-year-old male underwent a left thoracotomy, repair of esophageal vascular ring, and translocation of the left subclavian to the left carotid artery. Post-operative course was relevant for severe intractable left shoulder and left arm pain associated with allodynia and hyperalgesia. A supraclavicular catheter was inserted, and an infusion of ropivacaine 0.2% was started. The child was sent for physical therapy as he gradually regained all functions of his left arm and resumed his regular activities. Conclusion: Continuous supraclavicular brachial plexus catheter infusion of local anesthetic is a valuable method of reducing pain in severe cases of upper extremity pediatric CRPS and may be safer and more effective than other invasive measures such as sympathetic blocks and epidural catheterization. Further research surrounding the diagnosis and treatment of pediatric CRPS is needed to allow early diagnosis and treatment and to improve outcome.
Background
In a small radioligand-binding study of cutaneous α1-adrenoceptors in complex regional pain syndrome (CRPS), signal intensity was greater in the CRPS-affected limb than in controls. However, it was not possible to localize heightened expression of α1-adrenoceptors to nerves, sweat glands, blood vessels, or keratinocytes using this technique.Methods
To explore this in the present study, skin biopsies were obtained from 31 patients with CRPS type I and 23 healthy controls of similar age and sex distribution. Expression of α1-adrenoceptors on keratinocytes and on dermal blood vessels, sweat glands, and nerves was assessed using immunohistochemistry.Resultsα1-Adrenoceptors were expressed more strongly in dermal nerve bundles and the epidermis both on the affected and contralateral unaffected side in patients than in controls (P < 0.05). However, expression of α1-adrenoceptors in sweat glands and blood vessels was similar in patients and controls. α1-Adrenoceptor staining intensity in the CRPS-affected epidermis was associated with pain intensity (P < 0.05), but a similar trend for nerve bundles did not achieve statistical significance.DiscussionEpidermal cells influence nociception by releasing ligands that act on sensory nerve fibers. Moreover, an increased expression of α1-adrenoceptors on nociceptive afferents has been shown to aggravate neuropathic pain. Thus, the heightened expression of α1-adrenoceptors in dermal nerves and epidermal cells might augment pain and neuroinflammatory disturbances after tissue injury in patients with CRPS type I.
After peripheral nerve injury, nociceptive afferents acquire an abnormal excitability to adrenergic agents, possibly due to an enhanced expression of α1-adrenoceptors (α1-AR) on these nerve fibres. To investigate this in the present study, changes in α1-AR expression on nerve fibres in the skin and sciatic nerve trunk were assessed using immunohistochemistry in an animal model of neuropathic pain involving partial ligation of the sciatic nerve. In addition, α1-AR expression on nerve fibres was examined in painful and unaffected skin of patients who developed complex regional pain syndrome after a peripheral nerve injury (CRPS type II). Four days after partial ligation of the sciatic nerve, α1-AR expression was greater on dermal nerve fibres that survived the injury than on dermal nerve fibres after sham surgery. This heightened α1-AR expression was observed on non-peptidergic nociceptive afferents in the injured sciatic nerve, dermal nerve bundles and the papillary dermis. Heightened expression of α1-AR in dermal nerve bundles after peripheral nerve injury also co-localised with neurofilament 200, a marker of myelinated nerve fibres. In each patient examined, α1-AR expression was greater on nerve fibres in skin affected by CRPS than in unaffected skin from the same patient or from pain-free controls. Together, these findings provide compelling evidence of an up-regulation of α1-ARs on cutaneous nociceptive afferents after peripheral nerve injury. Activation of these receptors by circulating or locally secreted catecholamines might contribute to chronic pain in CRPS type II.
Complex regional pain syndrome (CRPS) is a term used to describe a variety of disorders characterized by spontaneous or stimulus-induced pain that is disproportional to the inciting event and accompanied by a myriad of autonomic and motor disturbances in highly variable combinations. There are no standards which can be applied to the diagnosis and would fulfill definitions of evidence-based medicine. Indeed, there are almost as many diagnostic criteria as there are names to this disorder. The umbrella term CRPS has been subdivided into type I and type II. CRPS I is intended to encompass reflex sympathetic dystrophy and similar disorders without a nerve injury; while CRPS II occurs after damage to a peripheral nerve. There are numerous etiological pathophysiological events that have been incriminated in development of CRPS, including inflammation, autoimmune responses, abnormal cytokine production, sympathetic-sensory disorders, altered blood flow and central cortical reorganization. However, the number of studies that have included appropriate controls and have sufficient numbers of patients to allow statistical analysis with appropriate power calculations is vanishingly small. This has led to over-diagnosis and often excessive pharmacotherapy and even unecessary surgical interventions. In this review we provide a detailed critical overview of not only the history of CRPS, but also the epidemiology, the clinical features, the pathophysiological studies, the proposed criteria, the therapy and, in particular, an emphasis that future research should apply more rigorous standards to allow a better understanding of CRPS, i.e. what it is, if it is, and when it is.
Algodystrophy or type I complex regional pain syndrome of the hand is characterized by regional vascular abnormalities with hyperpermeability, followed by a local colonization of fibroblasts after an initiating noxious event, e.g. the Pouteau-Colles fracture. Its typical natural clinical course is divided into three sequential stages: acute or pseudoinflammatory, then dystrophic, and at least atrophic. The pain is continuous and is accentuated with the use of the joints. Spontaneous pain, allodynia, hyperalgesia, and/or hyperpathia are outside the territory of a single peripheral nerve and disproportionate to the original event. There is regional evidence of edema, skin blood flow abnormality and abnormal sudomotor activity. Transient vascular hyperpermeability in the affected part is demonstrated by the three-bone scan features. 99mTechnetium EHDP bone scan provides an evaluation of the vascular abnormalities and of the osteoblastic activity. Some patients, especially female adolescent or young female patients, may have no bone edema in the affected extremity, and in these cases, bone scans reveal a low uptake in comparison with the other side and MRI signs are lacking. Local demineralization when present is demonstrated by X-rays, computed tomography, and bone mineral density and bone mineral content measurements. The amount of bone loss in algodystrophy in a few weeks or months can be very important. Trabecular fractures, or aseptic osteonecrosis are discussed in the differential diagnosis but their occurrence is rare in this localization. The best treatment against algodystrophy, especially of the hand remains to be discovered.
La algodistrofia o síndrome doloroso regional complejo de tipo I se caracteriza por anomalías vasculares con hiperpermeabilidad y colonización de fibroblastos, la mayoría de las veces limitadas a un miembro, un segmento de miembro o una zona aún más reducida. A partir de un episodio iniciador, primero se afecta la región distal. La evolución natural suele dividirse en tres estados: agudo o seudoinflamatorio, distrófico y atrófico. El dolor, desproporcionado respecto al episodio inicial, es continuo y se intensifica al tratar de movilizar las articulaciones afectadas. El dolor espontáneo, la alodinia, la hiperalgesia y/o la hiperpatía no se limitan al territorio de un solo nervio periférico. El edema, las anomalías del flujo vascular cutáneo y las anomalías sudomotoras son perceptibles desde el punto de vista clínico por las lesiones distales o mesomélicas. La hiperpermeabilidad vascular transitoria en la zona afectada se demuestra por resonancia magnética (RM) y gammagrafía ósea en tres fases. Algunos pacientes (adultos jóvenes y, sobre todo, adolescentes de sexo femenino) desarrollan una forma inicialmente fría con manifestaciones dolorosas, pero sin edema y con hipocaptación del trazador gammagráfico en comparación con el lado contrario. La RM es normal. La desmineralización ósea, tardía e inconstante, se demuestra mediante las radiografías simples comparativas y la tomografía computarizada (TC). En semanas o meses, la pérdida ósea puede ser comparable a la que se observa en una osteoporosis común de 10 años de evolución. Un episodio inaugural frecuente de la algodistrofia es una fractura cortical u oculta (fractura cortical y/o trabecular), pero los pacientes que sufren de algodistrofia también pueden portar una desmineralización prolongada y, por lo tanto, tener el riesgo de desarrollar una fractura. Para el diagnóstico diferencial se tienen en cuenta la causalgia, las fracturas trabeculares, la osteoporosis transitoria, la retracción capsular y la osteonecrosis aséptica. El tratamiento de un paciente afectado de algodistrofia es difícil, debido a la falta de una terapéutica validada.
Although sensory and autonomic nerve fibres generally do not interact directly, both may exert influences on blood flow during inflammation. For example, the sympathetic neurotransmitter noradrenaline/norepinephrine evokes axon reflexes, a response that involves release of vasoactive neuropeptides from the peripheral terminals of primary nociceptive afferent fibres. As well as boosting inflammation, this mechanism could play a role in normal renal function and heat dispersal from the skin. In certain disease states, aberrant communication between sensory and autonomic nerves might not only aggravate symptoms but also contribute to clinical deterioration by altering local circulatory dynamics. For example, in certain forms of neuropathic pain, an aberrant expression of α1-adrenoceptors on primary nociceptive afferents may provide a framework for cross-talk between sensory and autonomic nerve fibres. In addition to evoking pain and other unpleasant symptoms, this cross-talk could aggravate inflammation and disrupt nutritive perfusion of affected tissues. Finally, in disorders such as cluster headache, intense bursts of trigeminal nociceptive activity may trigger trigeminal-parasympathetic vasodilator reflexes which, in turn, provoke secondary vascular disturbances that amplify pain. A clearer understanding of sensory-autonomic interactions both in health and disease may provide a basis for new treatment approaches for conditions that respond poorly to conventional treatments.
Polyneuropathy can be linked to chronic pain but also to reduced pain sensitivity. We investigated peripheral C-nociceptors in painful and painless polyneuropathy patients to identify pain-specific changes. Eleven polyneuropathy patients with persistent spontaneous pain and 8 polyneuropathy patients without spontaneous pain were investigated by routine clinical methods. For a specific examination of nociceptor function, action potentials from single C-fibres including 214 C-nociceptors were recorded by microneurography. Patients with and without pain were distinguished by the occurrence of spontaneous activity and mechanical sensitization in C-nociceptors. The mean percentage of C-nociceptors being spontaneously active or mechanically sensitized was significantly higher in patients with pain (mean 40.5% and 14.6%, respectively, P=.02). The difference was mainly due to more spontaneously active mechanoinsensitive C-nociceptors (operationally defined by their mechanical insensitivity and their axonal characteristics) in the pain patients (19 of 56 vs 6 of 43; P=.02). The percentage of sensitized mechanoinsensitive C-nociceptors correlated to the percentage of spontaneously active mechanoinsensitive C-nociceptors (Kendall's tau=.55, P=.004). Moreover, spontaneous activity of mechanoinsensitive C-nociceptors correlated to less pronounced activity-dependent slowing of conduction (Kendall's tau=-.48, P=.009), suggesting that axons were included in the sensitization process. Hyperexcitability in mechanoinsensitive C-nociceptors was significantly higher in patients with polyneuropathy and pain compared to patients with polyneuropathy without pain, while the difference was much less prominent in mechanosensitive (polymodal) C-nociceptors. This hyperexcitability may be a major underlying mechanism for the pain experienced by patients with painful peripheral neuropathy.
Unlabelled:
Spontaneous pain is often discussed in the context of both chronic inflammatory and neuropathic pain conditions, and it has been suggested that spontaneous pain, rather than stimulus-evoked pain, may be the more significant clinical problem. The following issues are discussed here. First, it is suggested that the concept of spontaneous pain makes no sense when the pain is the result of an ongoing inflammatory reaction. Evidence is reviewed that indicates that spontaneous pain is present in patients with neuropathic pain, but perhaps only in a subset of such patients. Second, it is suggested that in the presence of allodynia and hyperalgesia, stimulation from the activities of daily life occurs very many times a day and that these stimulus-evoked pains may summate to give a fluctuating level of daily pain that both patients and investigators mistake for spontaneous pain.
Perspective:
Which is more important-stimulus-evoked pain or spontaneous pain? This review suggests that to answer the question we will need to distinguish neuropathic spontaneous pain from inflammatory ongoing pain and to differentiate both from summated allodynic and hyperalgesic pains caused by the stimuli of daily life.
1. We recorded from centrally connected axons isolated from the proximal stump of the sciatic nerve in intact rats and in rats whose nerves had been transected 4 days-6 mo previously. Afferent axons selected for study had spontaneous impulse activity that originated ectopically in dorsal root ganglia (DRGs) L4 and L5. The sympathetic supply of these DRGs was excited by repetitive electrical stimulation of ventral roots T13 and L1. We examined quantitatively changes in afferent ongoing firing evoked by sympathetic stimulation. Results are based on observations from 161 neurons in rats with sciatic nerve injury and from 58 neurons in control rats with intact sciatic nerves. Of these 219 neurons, 204 had myelinated fibers (A neurons) and 15 had unmyelinated fibers (C neurons), on the basis of measurements of conduction velocity. 2. In rats with nerve injury the majority of the spontaneously active neurons tested (95 of 161) responded to sympathetic stimulation with a change in ongoing firing frequency: 41 neurons exhibited a significant increase in discharge frequency that was often followed by suppression (28 of 41), and 54 neurons responded with a decrease in ongoing activity (simple suppression). In control rats, in contrast, only 1 of the 58 spontaneously active sensory neurons tested responded to sympathetic stimulation. 3. In A neurons, the response pattern changed systematically with time after sciatic nerve injury. At 4-22 days after nerve lesion, excitation was much more common than suppression. At 60-93 days, excitation and suppression occurred about equally. At 110-171 days, suppression was by far the more common response. 4. Of the 14 C neurons, 2 were excited by sympathetic stimulation (at 4-22 days postoperative) and 10 were suppressed (2 at 4-22 days, 8 at > 60 days). The only spontaneously active C neuron found in control rats was not affected by sympathetic stimulation. 5. The magnitude of responses in the three postoperative intervals investigated was similar. This was so for both the excitatory and the simple suppressive responses. The average latency between onset of stimulation and excitatory responses in afferent A fibers (approximately 10 s) was significantly less than the latency to simple suppressive responses (approximately 20 s). 6. The mean spontaneous firing rate of A neurons decreased with time after nerve lesion. No change was observed in C neuron activity. The mean firing rate of A neurons was significantly higher than that of C neurons 4-93 days after nerve lesion, but not later. In all three postoperative periods investigated, the mean rate of spontaneous activity was the same in A neurons that responded to sympathetic stimulation and A neurons that did not. 7. The results show that nerve injury triggers sympathetic-sensory coupling within rat DRGs. Excitatory coupling is preferentially present in the period shortly after nerve injury, and is subsequently replaced by suppressive coupling. This suggests that there is a gradual change in the underlying coupling mechanism.
Experimental and clinical studies in animals and humans have indicated that nociceptive nerve fibres can acquire sensitivity to norepinephrine after injury or chemical sensitization. To evaluate the functional relevance of such sensitization, we recorded the activity of single polymodal C-fibre afferents in healthy human volunteers and investigated whether intense physiological sympatho-excitation could affect their firing properties. This was studied before and after chemical sensitization of receptive fields by topical application of mustard oil. All afferent C fibres investigated (11 units in 10 subjects) were mechano-heat-sensitive, and four of seven fibres subjected to mustard oil were also chemosensitive. Putative sensitivity to sympathetic stimulation was investigated during low-frequency (0.25 Hz) electrical stimulation of the unit receptive field at a threshold intensity sufficient to evoke an action potential in the afferent fibre after every second to third stimulus. Following a prolonged period of silent rest, sympathoexcitation was elicited by forced mental arithmetic for 60 s, again followed by a long silent rest period. During stress, sympathetic nerve traffic increased to 625 +/- 146% of the control level, while firing of the afferent units remained unchanged. There was no sign of sympathetically mediated direct activation of afferent units and no change in the relative amounts of afferent activations caused by the background electrical stimulation. Results were similar for all units, both before (seven units in six subjects) and after (seven units in seven subjects) chemical sensitization of their cutaneous receptive field. The results suggest that if chemical sensitization of nociceptive C afferent neurons with mustard oil does induce sensitivity to noradrenaline in humans, it is not sufficient to make C nociceptive fibres respond to short-lasting physiological variations in sympathetic outflow.
Burning pain was induced in healthy human subjects by intracutaneous injections of capsaicin (20 microl, 0.1%) in the innervation territory of the cutaneous branch of the peroneal nerve and the pain responses were compared with the activation patterns of afferent C-fibres recorded by microneurography. Responsiveness of single units to mechanical or heat stimuli or to sympathetic reflex provocation tests was determined by transient slowing of conduction velocity following activation (marking technique). Capsaicin activated each of 12 mechano-responsive and 17 of 20 mechano-insensitive C-units. However, the duration of the responses to capsaicin was significantly longer in mechano-insensitive C-units (median 170 s; quartiles 80-390) compared with mechano-responsive C-units (8 s; 4-10). The activation times of mechano-insensitive C-units closely matched the duration of capsaicin-induced pain responses, whereas activation of mechano-responsive C-units was too short to account for the duration of the burning pain. The latter generally were desensitized to mechanical stimulation at the injection site, whereas 8 of 17 of the originally mechano-insensitive C-units became responsive to mechanical probing at the injection site after capsaicin. Responses typically started several seconds after the onset of the mechanical stimulus in parallel with pain sensations. We did not observe sensitization to brushing or to punctate stimuli in uninjured parts of the innervation territory. Differential capsaicin sensitivity adds to the cumulating evidence for the existence of two categories of functionally different nociceptors in human skin, with a special role for mechano-insensitive fibres in sensitization and hyperalgesia. Possible structural differences between these two categories are discussed, including the role of tetrodotoxin-resistant sodium channels.
Peripheral nociceptor sensitization is accepted as an important mechanism of cutaneous primary hyperalgesia, but secondary hyperalgesia has been attributed to central mechanisms since evidence for sensitization of primary afferents has been lacking. In this study, microneurography was used to test for changes in sensitivity of C nociceptors in the area of secondary hyperalgesia caused by intradermal injection of capsaicin in humans. Multiple C units were recruited by electrical stimulation of the skin at 0.25 Hz and were identified as discrete series of dots in raster plots of spike latencies. Nociceptors slowed progressively during repetitive stimulation at 2 Hz for 3 min. According to their response to mechanical stimulation, nociceptors could be classified as either mechano-sensitive (CM) or mechano-insensitive (CM(i)). These two nociceptor subtypes had different axonal properties: CM(i) units slowed by 2% or more when stimulated at 0.25 Hz after a 3-min pause, whereas CM units slowed by <1%. This stimulation protocol was used before capsaicin injection to identify nociceptor subtype without repeated probing, thus avoiding possible mechanical sensitization. Capsaicin, injected 10-50 mm away from the site of electrical stimulation, had no effect on any of 29 CM units, but induced bursts of activity in 11 of 15 CM(i) units, after delays ranging from 0.5 to 18 min. The capsaicin injections also sensitized a majority of the CM(i) units, so that 11 of 17 developed immediate or delayed responsiveness to mechanical stimuli. This sensitization may contribute a peripheral C fiber component to secondary hyperalgesia.
Neuropathic and inflammatory pain can be modulated by the sympathetic nervous system. In some pain models, sympathetic postganglionic efferents are involved in the modulation of nociceptive transmission in the periphery. The purpose of this study is to examine the sensitization of Adelta- and C-primary afferent nociceptors induced by intradermal injection of capsaicin (CAP) to see whether the presence of sympathetic efferents is essential for the sensitization. Single primary afferent discharges were recorded from the tibial nerve after the fiber types were identified by conduction velocity in anesthetized rats. An enhanced response of some Adelta- and most C-primary afferent fibers to mechanical stimuli was seen in sham-sympathectomized rats after CAP (1%, 15 mul) injection, but the enhanced responses of both Adelta- and C-fibers were reduced after sympathetic postganglionic efferents were removed. Peripheral pretreatment with norepinephrine by intraarterial injection could restore and prolong the CAP-induced enhancement of responses under sympathectomized conditions. In sympathetically intact rats, pretreatment with an alpha(1)-adrenergic receptor antagonist (terazosin) blocked completely the enhanced responses of C-fibers after CAP injection in sympathetically intact rats without significantly affecting the enhanced responses of Adelta-fibers. In contrast, a blockade of alpha(2)-adrenergic receptors by yohimbine only slightly reduced the CAP-evoked enhancement of responses. We conclude that the presence of sympathetic efferents is essential for the CAP-induced sensitization of Adelta- and C-primary afferent fibers to mechanical stimuli and that alpha(1)-adrenergic receptors play a major role in the sympathetic modulation of C-nociceptor sensitivity in the periphery.
This double-blind, randomized, multicenter study was designed to determine the short-term and long-term efficacy of intravenous regional block with guanethidine in patients with reflex sympathetic dystrophy (RSD)/causalgia. Sixty patients were enrolled to receive four intravenous regional blocks at 4-day intervals with either guanethidine or placebo in 0.5% lidocaine. Each patient was randomized to receive either one, two, or four blocks with guanethidine. Follow-up visits were scheduled for 4 days, 1 mo, 3 mo, and 6 mo after their final block. At 4 days after the initial block, the group treated with placebo experienced a greater decrease in pain scores than those treated with guanethidine, although this difference was not statistically significant. On long-term followup there was no difference in pain scores between groups receiving one, two, or four guanethidine blocks. Overall, only 35% of patients experienced clinically significant relief on long-term followup even though all were treated early in the evolution of RSD.
(Anesth Analg 1995;81:718-23)
Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining; the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of N-13-ammonia was used to assess local perfusion, and 6-[F-18]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. N-13-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[F-18]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[F-18]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydrophenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows.
This chapter presents preliminary observations of a study on the pathophysiology of hyperalgesia in the causalgic pain syndrome. There were four patients, two males and two females, 25–50 years of age. At the time of investigation, they had suffered from causalgia for 3–10 years. In the males, the causalgia developed after crush injuries to the right foot in one case and the right hand in the other. In one female, causalgia occurred in the left half of the chest after mastectomy with axillary dissection. The other female developed causalgia twice, the first time in the left hand and forearm after surgical damage to the lateral cutaneous nerve of the forearm, and the second time in the left shoulder following the sympathectomy that relieved the pain in her hand and forearm. The multiunit sympathetic activity had qualitatively normal characteristics, both at rest and in response to arousal stimuli and mental stress, which are known to increase cutaneous sympathetic activity in normal subjects.
Burning pain was induced in healthy human subjects by intracutaneous injections of capsaicin (20 μl, 0.1%) in the innervation territory of the cutaneous branch of the peroneal nerve and the pain responses were compared with the activation patterns of afferent C-fibres recorded by microneurography. Responsiveness of single units to mechanical or heat stimuli or to sympathetic reflex provocation tests was determined by transient slowing of conduction velocity following activation (marking technique). Capsaicin activated each of 12 mechano-responsive and 17 of 20 mechano-insensitive C-units. However, the duration of the responses to capsaicin was significantly longer in mechano-insensitive C-units (median 170 s; quartiles 80–390) compared with mechano-responsive C-units (8 s; 4–10). The activation times of mechano-insensitive C-units closely matched the duration of capsaicin-induced pain responses, whereas activation of mechano-responsive C-units was too short to account for the duration of the burning pain. The latter generally were desensitized to mechanical stimulation at the injection site, whereas 8 of 17 of the originally mechano-insensitive C-units became responsive to mechanical probing at the injection site after capsaicin. Responses typically started several seconds after the onset of the mechanical stimulus in parallel with pain sensations. We did not observe sensitization to brushing or to punctate stimuli in uninjured parts of the innervation territory. Differential capsaicin sensitivity adds to the cumulating evidence for the existence of two categories of functionally different nociceptors in human skin, with a special role for mechano-insensitive fibres in sensitization and hyperalgesia. Possible structural differences between these two categories are discussed, including the role of tetrodotoxin-resistant sodium channels.
Experimental and clinical studies in animals and humans have indicated that nociceptive nerve fibres can acquire sensitivity to norepinephrine after injury or chemical sensitization. To evaluate the functional relevance of such sensitization, we recorded the activity of single polymodal C-fibre afferents in healthy human volunteers and investigated whether intense physiological sympatho-excitation could affect their firing properties. This was studied before and after chemical sensitization of receptive fields by topical application of mustard oil. All afferent C fibres investigated (11 units in 10 subjects) were mechano-heat-sensitive, and four of seven fibres subjected to mustard oil were also chemosensitive. Putative sensitivity to sympathetic stimulation was investigated during low-frequency (0.25 Hz) electrical stimulation of the unit receptive field at a threshold intensity sufficient to evoke an action potential in the afferent fibre after every second to third stimulus. Following a prolonged period of silent rest, sympathoexcitation was elicited by forced mental arithmetic for 60 s, again followed by a long silent rest period. During stress, sympathetic nerve traffic increased to 625 ± 146% of the control level, while firing of the afferent units remained unchanged. There was no sign of sympathetically mediated direct activation of afferent units and no change in the relative amounts of afferent activations caused by the background electrical stimulation. Results were similar for all units, both before (seven units in six subjects) and after (seven units in seven subjects) chemical sensitization of their cutaneous receptive field. The results suggest that if chemical sensitization of nociceptive C afferent neurons with mustard oil does induce sensitivity to noradrenaline in humans, it is not sufficient to make C nociceptive fibres respond to short-lasting physiological variations in sympathetic outflow.
This chapter concentrates on the mechanisms by which the sympathetic nervous system may be causally involved in the generation of pain and hyperalgesia following nerve lesion and of pain, hyperalgesia, and the neurogenic component during inflammation following tissue trauma. Emphasis is put on the possible differences in the mechanisms by which the sympathetic nervous system may be involved in pain following nerve trauma and pain following tissue trauma associated with inflammation. Several clinical observations indicate that the sympathetic nervous system may be involved in different pain states. The chapter describes clinical observations that support this idea for patients with sympathetically maintained pain following nerve trauma and patients with pain during inflammation not associated with overt nerve injury. It has been experimentally shown that the sympathetic post-ganglionic neurons supplying skin and synovium have important functions in the sensitization and activation of primary afferent neurons, as well as in neurogenic inflammation under pathophysiological conditions. These peripheral functions of the post-ganglionic neurons are under control of the central nervous system.
Bei Patienten mit sympathisch unterhaltenem Schmerz (SMP) und ausgeprägten autonomen Störungen (Hautdurchblutung) einer Extremität
zeigen mikroneurographische Ableitungen, die simultan an der betroffenen und der gesunden Seite durchgeführt wurden, keine
Seitendifferenzen der sympathischen Aktivität. Diese Ergebnisse sprechen gegen die Hypothese, daß ein SMP auf ein verändertes
sympathisches Reflexmuster an der betroffenen Extremität zurückzuführen ist. Sie zeigen vielmehr, daß die autonomen Störungen
an den Effektororganen keine sichere Aussage über die Aktivität sympathischer Neuronen zulassen.
In simultaneous bilateral nerve recordings, patients with Sympathetically Maintained Pain (SMP) affecting one limb show similar
sympathetic traffic in nerves supplying the affected and unaffected limb, also when the painful limb shows a marked regional
autonomic (vasomotor) dysfunction. These findings argue against the notion that SMP must be mediated by a reflex change in
the pattern of sympathetic discharge. In general, they underline the fact that autonomic effector disturbances may give little
information about underlying nerve traffic.
Physiological changes in the nervous system occur with ageing. Both a decline of function and a decrease in the number of C-fibres in the skin have been reported for healthy aged subjects. With the use of microneurographic recordings from single C-fibres in humans we have compared the sensory and axonal properties of these neurones in young and aged healthy subjects. A total of 146 C-fibres were recorded from the common peroneal nerve in young subjects (mean age 24.7 years) and 230 C-fibres were recorded in aged subjects (mean age 56.2 years). In aged subjects, changes were found in the composition of the C-fibre population and in sensory and axonal properties. The relative incidence of afferent to efferent C-fibres was relatively constant independent of the age of subjects. The ratio of mechano-responsive to mechano-insensitive nociceptors was approximately 8 : 2 in the young controls while in aged subjects it was 7 : 3. In aged subjects 13% of the fibres showed atypical discharge characteristics, while this was not observed in young subjects. Spontaneous activity, sensitization and loss of sensory function were found regularly. Changes in functions of the conductile membrane were also observed in fibres from aged subjects. The degree of activity-dependent conduction velocity slowing in response to high frequency stimulation (2 Hz) was more pronounced, while the normalization of conduction velocity subsequent to high frequency stimulation was protracted. We found that both sensitization and desensitization or degeneration of afferent C-fibres occur with age, but are still rare compared to patients with neuropathy. The changes in the axonal properties of C-fibres in aged subjects are compatible with hypoexcitability of the fibres. These findings are important for the understanding and differential diagnoses regarding pathological processes and normal ageing.
In various chronic painful states, the sympathetic nerve supply was blocked either by injecting the sympathetic chain and ganglia with local anaesthesia or by the injection of guanethidine during occlusion of the circulation. There was a striking relation between the presence of hyperpathia and the relief of pain by the blocks. The sympathetic block was unlikely to relieve the pain unless hyperpathia accompanied the pain; when hyperpathia was present, a sympathetic block relieved both the constant pain and the hyperpathia. The effectiveness of the guanethidine blocks shows that the pain and the hyperpathia are maintained by the emission of noradrenaline in the periphery. The facts related to the sympathetic system and sensibility are discussed.
Nociceptive primary afferents develop an increased responsiveness in inflamed tissue. The aim of this neurophysiological investigation was to study the sensitivity changes of cutaneous nociceptors following application of the algesic inflammatory mediator bradykinin and to examine a possible contribution of the sympathetic nervous system. Single unit recordings were obtained in a skin-nerve in vitro preparation from unmyelinated nociceptive afferents supplying the hairy skin of intact or of chronically sympathectomized rats. In preparations from intact skin, mechano-heat-sensitive C-fibres responding to superfusion of the receptive fields with 10 microM bradykinin for 1 min were sensitized to heat stimulation 2 min later. On average, the threshold dropped by 5.0 degrees C, the maximal discharge frequency increased by 34% and the temperature eliciting this peak discharge dropped by 5.6 degrees C. This resulted in a leftward shift and an increased slope of the stimulus-response function indicating sensitization. In surgically sympathectomized animals, 52% of the nociceptive afferents were activated by bradykinin which is not different from normal controls. In sympathectomized animals neither the reduction of the mean threshold (4.6 degrees C) nor the increase of the peak discharge frequency (48%) differed significantly from intact controls. The change of the stimulation-response function following bradykinin application was virtually identical in intact and sympathectomized preparations. Moreover, bradykinin increased the heat discharge of individual fibres by a factor of 2.1 in intact and 1.9 in sympathectomized animals, respectively. In both preparations the increased responsiveness of the nociceptors was short-lived and had resolved 7 min after chemical stimulation.(ABSTRACT TRUNCATED AT 250 WORDS)
In animal neuroma models the application of alpha-adrenergic agonists causes a burst of spontaneous afferent activity. The increased activity has been hypothesized to generate nociceptive input. Corroborative work in humans, however, has not been done. Nine subjects with chronic nerve end neuromas received perineuromal injections of normal saline, epinephrine (5 micrograms), and lidocaine in a blinded manner. Qualitative and quantitative pain assessments were performed with each injection. Epinephrine, but not saline, caused an intense increase in reported pain with subjects often commenting that the appendage was "on fire". Lidocaine significantly reduced but did not completely abolish the reported pain. The chemosensitivity of the neuroma to epinephrine may explain some of the clinical responses noted after sympathetic system manipulation. It is likely that alpha-adrenergic sensitivity is only one of many components sustaining or exacerbating pain after nerve injury.
The mechanisms by which peripheral nerve injuries sometimes lead to causalgia, aberrant burning pain peripheral to the site
of nerve damage, are uncertain, although the sympathetic nervous system is known to be involved. Whether such syndromes could
be the result of the development of responsiveness by some cutaneous pain receptors (C-fiber nociceptors) to sympathetic efferent
activity as a consequence of the nerve injury was tested in an animal model. After nerve damage but not in its absence, sympathetic
stimulation and norepinephrine were excitatory for a subset of skin C-fiber nociceptors and enhanced the responsiveness of
these nociceptors to tissue-damaging stimulation. These effects were demonstratable within days after nerve lesions, occurred
at the cutaneous receptive terminal region, were manifest in sensory fibers that had not degenerated after the injury, and
were mediated by alpha 2-adrenergic-like receptors.
Primary afferent units in the saphenous nerve of cats, functionally identified as A-delta myelinated nociceptors, were tested for their responses to stimulation of the sympathetic trunk. The units were subdivided functionally into A-mechano-heat receptors (AMHs), which respond to both noxious heat and pressure, and high-threshold mechanoreceptors (HTMs), which respond only to pressure. No units of either subdivision were activated by sympathetic stimulation (SS) prior to noxious heating of their receptive fields. However, six of the seven AMH units with the highest mechanical thresholds (greater than 5 g von Frey) were activated by SS alone (10 Hz) after they had been sensitized by noxious heating of their receptive fields. Sensitized AMH units with lower mechanical thresholds (less than 5 g) were generally not activated by SS alone (1 of 22 units), and their responses to warming of their receptive fields were not altered by SS. The excitatory sympathetic action on AMH units was abolished by alpha- but not beta-andrenergic blockade in the two units tested. HTMs were unresponsive to SS even after repeated noxious heating of their receptive fields (15 units tested). The results of this study indicate that relatively high rates of sympathetic efferent activity (10 Hz) can induce firing in a small population of AMH receptors in damaged skin, specifically those units with high mechanical thresholds. This sympathetically evoked activity might trigger or exacerbate pain associated with skin damage; however, functional conclusions are difficult to draw, because of the scarcity of such units and the fact that the responses in some were brief and of low firing rates.
A hypothesis is presented concerning the neuronal mechanisms which subserve the sympathetically maintained pains such as causalgia and reflex sympathetic dystrophy. The hypothesis rests on two assumptions: that a high rate of firing in spinal wide-dynamic-range (WDR) or multireceptive neurons results in painful sensations; and that nociceptor responses associated with trauma can produce long-term sensitization of WDR neurons. The hypothesis states that chronic sympathetically maintained pains are mediated by activity in low-threshold, myelinated mechanoreceptors, that this afferent activity results from sympathetic efferent actions upon the receptors or upon afferent fibers ending in a neuroma and that these afferent fibers evoke sufficient activity in sensitized spinal WDR neurons to produce a painful sensation. This hypothesis is based on known characteristics of these neuronal populations studied in experimental animals and on the observed sensory disturbances reported in patients successfully treated with sympathetic blocks. This hypothesis does not require nerve injury or dystrophic tissue. It explains both the continuous pain and the allodynia that are common to these syndromes and their abolition by sympathetic block. Specific changes are proposed in the diagnosis and treatment of post-traumatic pains.
Neuroma-in-continuity was experimentally produced in cats by suturing the proximal stump of a transected hindlimb cutaneous nerve to the distal stump of the transected tibial nerve. Eleven to 20 months afterwards single non-myelinated fibres were identified by electrical recording from filaments of the nerves proximally from the neuroma. When tested with repetitive electrical stimulation of the lumbar sympathetic trunk (LST) or i.v. injections of adrenaline, C-fibres in 14 out of 30 filaments were excited by at least one of these stimuli (12 by adrenaline, 7 by stimulation of LST). The fibres responding to LST stimulation were already substantially excited by low frequency stimulation (1-2 Hz). During systemic hypoxia known to result in reflex increases of efferent sympathetic activity responses were elicited in 4 out of 6 C-fibres. Thus, stimuli simulating physiological conditions of sympathetic activity can excite afferent C-fibres in a chronically lesioned nerve.
Single unit activity in sympathetic nerve fibres was studied in microelectrode recordings from intact cutaneous nerves in alert man. 4 units exhibited a “spontaneous” discharge of very low frequency (not exceeding 15 imp/min) during resting conditions, whereas 4 other units were silent. Mental concentration and arousal stimuli of different types caused an increase in impulse frequency of spontaneously active units, and previously silent units started firing. In reflex responses to electrical shocks, deep breathing and loud noises, single units often fired repeatedly in bursts, the maximal instantaneous frequency observed being 35 imp/s. Intense reflex responses to electrical stimulation were sometimes followed by a suppression of spontaneous activity for 1–2 s. Some of the units probably had a sudomotor function, since the unit activity correlated well with changes in galvanic skin resistance recorded within the innervation zone of the explored nerve fascicle. The conduction velocity measured for 6 sympathetic units ranged 1.0–0.58 m/s.
A technique is described which allows recording of multi-fiber discharge and single-unit activity from intact peripheral nerves of awake human subjects. A tungsten electrode with a tip diameter of 5–15 μ was driven manually through skin, subcutaneous tissues and nerve sheath. From many recording sites in mixed nerve trunks neural impulses with an amplitude of 40 μv were recorded in response to peripheral mechanical stimuli. It was possible to judge when afferent nerve fibers of cutaneous origin lay close to the electrode tip by the quality of the insertion paresthesias and the type of peripheral stimuli required to induce afferent responses. Examples are presented of fast and slowly adapting mass discharge induced by mechanical stimuli on glabrous and nonglabrous skin areas. When single-unit activity was discriminated it was often possible to determine the site of the cutaneous end organ, the discharge characteristics of the unit, and the conduction velocity of the nerve fiber. Ten such single-unit recordings are described.
The first aim was a systematic review of intravenous regional sympathetic blocks (IRSBs) in patients with reflex sympathetic dystrophy (RSD). Randomized controlled trials (RCTs) of IRSBs in patients with RSD were identified by MEDLINE search (1966 to May 1993) and by hand search of 30 journals (1950 to May 1993). Authors of eligible trials were asked for information on additional trials and for unpublished data. Seven RCTs of IRSBs in RSD were found. Four used guanethidine; none showed significant analgesic effect in IRSBs to relieve pain due to RSD. Two reports, one using ketanserin and one bretylium, with 17 patients in total, showed some advantage of IRSBs over control. RCT results were not combined because of the variety of different drugs and outcome measures and because of methodological deficiencies in most of the reports. The second aim was a randomized, double-blind, crossover study to assess the effectiveness of IRSBs with guanethidine. Patients fulfilling diagnostic criteria for RSD and who had reported pain relief after an open IRSB with guanethidine received IRSBs with guanethidine high dose, guanethidine low dose, and normal saline. Pain intensity and relief, adverse effects, mood, duration of analgesia, and global scores were recorded. Sixteen patients with diagnosis of RSD were recruited, but only nine entered the double-blind phase. The trial was stopped prematurely because of the severity of the adverse effects. No significant difference was found between guanethidine and placebo on any of the outcome measures.(ABSTRACT TRUNCATED AT 250 WORDS)
This double-blind, randomized, multicenter study was designed to determine the short-term and long-term efficacy of intravenous regional block with guanethidine in patients with reflex sympathetic dystrophy (RSD)/causalgia. Sixty patients were enrolled to receive four intravenous regional blocks at 4-day intervals with either guanethidine or placebo in 0.5% lidocaine. Each patient was randomized to receive either one, two, or four blocks with guanethidine. Follow-up visits were scheduled for 4 days, 1 mo, 3 mo, and 6 mo after their final block. At 4 days after the initial block, the group treated with placebo experienced a greater decrease in pain scores than those treated with guanethidine, although this difference was not statistically significant. On long-term followup there was no difference in pain scores between groups receiving one, two, or four guanethidine blocks. Overall, only 35% of patients experienced clinically significant relief on long-term followup even though all were treated early in the evolution of RSD.
To test for the presence of "sympathetically maintained pain" (SMP), we administered placebo-controlled phentolamine sympathetic blocks to 14 patients with painful polyneuropathies. Six received i.v. infusion of saline for 30 minutes, followed by phentolamine (35 mg). In eight patients, the saline phase was followed by double-blind infusion of phentolamine or phenylephrine (500 micrograms), a second saline phase, and then the other active drug. We measured magnitudes of spontaneous pain and mechanical hyperalgesias on a 0-to-10 pain scale every 5 minutes and monitored sensory and sympathetic effects clinically and through quantitative thermotest and thermography. Five patients reported significant diminution of pain (> 50%), all in response to placebo. Neither phentolamine nor phenylephrine provided relief, although all patients had signs of physiologic abnormalities reputed to be determinants or predictors of SMP. These results complement previous studies demonstrating the nonexistence of SMP among "reflex sympathetic dystrophy" patients and further question the concept of SMP.
Patients with "reflex sympathetic dystrophy" or "causalgia" underwent sympathetic blocks. In protocol A (77 patients), we infused placebo (saline) for 30 minutes followed by phentolamine (35 mg). In protocol B (23 patients), the saline phase was followed by double-blind infusion of phentolamine or phenylephrine (500 micrograms), a second phase of saline, and then the other active drug. We assessed magnitudes of pain and mechanical hyperalgesias on a 0-to-10 pain scale and monitored sensory and sympathetic effects. With protocol A, pain diminished significantly (> or = 50%) during placebo in 22 patients (28.9%) and during phentolamine in seven (9.2%). With protocol B, four patients (17.3%) had relief of pain during placebo, four (17.3%) during phenylephrine, and two (8.7%) during phentolamine. All "phentolamine responders" had progressive pain relief from placebo. Two patients expressed relief during phenylephrine and worsening during phentolamine. Most patients did not respond significantly to saline or drugs. Thus, pharmacologic manipulation of the alpha-1 adrenergic receptor by either agonist or antagonist drug does not influence neuropathic pains. These results raise questions about the existence of "sympathetically maintained pain," as diagnosed by sympathetic blocks improperly controlled for placebo.
We have tested the effects of cutaneous application of noradrenaline in 35 patients presenting with neuropathic pain. Depending on the outcome of sympatholytic interventions the patients were considered to have sympathetically maintained pain (SMP; n = 25) or sympathetically independent pain (SIP; n = 10). Iontophoretic application or cutaneous injection of noradrenaline into symptomatic skin aggravated pain and mechanical or thermal hyperalgesia in 7/25 SMP patients. Results from differential nerve blocks suggested that noradrenaline-induced ongoing pain and heat hyperalgesia were signalled by unmyelinated afferents, while touch-evoked pain and cold hyperalgesia were signalled by myelinated afferents. In none of the remaining 18/25 SMP patients, 10 SIP patients or 18 normal subjects did application of noradrenaline result in any appreciable increase of pain. A follow-up of 12 patients (initially 9 SMP, 3 SIP) after 12-16 years showed that one individual (previously SMP) was healthy, while 3 patients still suffered from SMP and 8 from SIP. Of the 5 SMP patients who had noradrenaline-induced pain at the initial examination, only 1 SMP patient still responded to noradrenaline with pain and hyperalgesia. Three other patients had changed to SIP and 1 individual was healthy. None of these 4 and none of the 7 initially noradrenaline-unresponsive patients experienced pain to the noradrenaline challenge at follow-up. Thus, cutaneous noradrenaline application can aggravate the pain in some, but not all SMP patients. THe abnormal noradrenaline reaction can change over time as can the pain relieving effects of sympatholytic therapy.
Sympathetic post-ganglionic neurons may be involved in the generation of pain, hyperalgesia and inflammation under pathophysiological conditions. Two categories of influence of the sympathetic neuron on afferent neurons can be distinguished and this distinction seems to be related to whether the coupling between afferent and sympathetic neuron develops after nerve lesion or after tissue trauma with inflammation (Fig. 15): A. Peripheral nerve lesion generates plastic changes of the afferent and sympathetic postganglionic neurons, depending on the type of nerve lesion (e.g. complete, partial). Both afferent and post-ganglionic neurons exhibit degenerative and regenerative changes and unlesioned neurons may show collateral sprouting in the periphery as well as in the dorsal root ganglion. This reorganization of the peripheral neurons may lead to chemical coupling between sympathetic and afferent neurons. The coupling is responsible for sensitization and/or activation of primary afferent neurons by the sympathetic neurons. The mediator probably is norepinephrine, but other substances cannot be excluded. The afferent neuron expresses or upregulates functional adrenoceptors. The type of adrenoceptor involved is probably alpha 2. The coupling may occur at different sites of the primary afferent neuron, e.g. at the lesion site, remote from the lesion site in the dorsal root ganglion or between nonlesioned sympathetic and afferent neurons which show collateral sprouting. The biochemical signals which trigger these changes probably are neurotrophic substances, their receptors which are synthesized by the peripheral neurons, Schwann cells and other cells in response to the peripheral lesions. B. Sympathetic nerve terminals in peripheral tissues may serve as mediator elements in hyperalgesia and inflammation following tissue trauma without nerve lesion. Experiments show that these functions are largely independent of activity in the sympathetic neurons and independent of vesicular release of transmitter substances (such as norepinephrine). Sensitization of nociceptive afferents for mechanical stimuli and venular plasma extravasation in the synovium which are induced by the inflammatory mediator bradykinin are, at least in part, dependent on the sympathetic terminal. The signal to venules and afferent receptors is synthesized and released from the sympathetic terminal or in association with it. It is a prostaglandin (probably PGE2). Sympathetically mediated (neurogenic) inflammation and neurogenic inflammation mediated by afferents may interact reciprocally and enhance the inflammatory process as well as the sensitization of nociceptive afferents. Norepinephrine may also lead to sensitization of nociceptive afferents under inflammatory conditions. This sensitization is presumably mediated by alpha 2-adrenoceptors in the sympathetic varicosities and by a prostaglandin (probably PGI2) which is synthesized and released by or in association with the sympathetic varicosities.
The effects of partial division of the great auricular nerve of adult rabbits were evaluated on the responsiveness of cutaneous C-fiber polymodal nociceptors (CPMs) to sympathetic stimulation (SS), close-arterial injections of epinephrine (EPI) and other alpha-adrenergic agonists. In normal unanesthetized rabbits, the two ears were usually at the same temperature. Two to 4 weeks after partial nerve lesions, however, the operated ear was cooler by 1-3 degrees C in the majority of animals, suggestive of increased vasoconstriction and possible denervation supersensitivity. Neither SS nor EPI (50 ng) excited CPM units (n = 23) from intact anesthetized animals. In contrast, 14-27 days after partial nerve lesions, SS (8 out of 38 units) and EPI (12 out of 38 units) were excitatory for a class of CPMs. There was notable variability in the response of different units and of a given unit between first and second trials. Responses consisted of 1-22 impulses for SS and 1-23 impulses for EPI in the 60 s following a trial. Arterial occlusion did not activate responsive units, suggesting that the excitation was not caused by vascular or temperature changes. Selective alpha2-adrenoceptor blockade with yohimbine (0.6-1.0 mg/kg i.v.) or rauwolscine (1.0 mg/kg i.v.) reversibly antagonized the effects of SS and EPI. EPI-responsive units were also excited by norepinephrine (50 ng) and guanabenz (10 microg) but not by clonidine (3 microg) or B-HT 933 (3 microg). The results suggest that circulating EPI, acting via an alpha-adrenoceptor subtype, can play a part in the development and/or maintenance of aberrant pain syndromes such as causalgia and other sympathetically related dystrophies.
1. Immunocytochemistry with polyclonal antibodies directed against specific fragments of intracellular loops of alpha2A- and alpha2C-adrenergic receptors (alpha2A-AR, alpha2C-AR) was used to explore the possibility that expression of these receptors in dorsal root ganglion (DRG) neurones of rat alters as a result of peripheral nerve injury or localized inflammation. 2. Small numbers of neurones with positive alpha2A-AR immunoreactivity (alpha2A-AR-IR) were detected in DRG from normal animals or contralateral to nerve lesions. In contrast, after complete or partial sciatic nerve transection the numbers of ipsilateral L4 and L5 DRG somata expressing alpha2A-AR-IR sharply increased (>5-fold). There was no discernible change in the number of DRG neurones exhibiting alpha2A-AR-IR innervating a region in association with localized chemically induced inflammation. 3. After nerve injury, double labelling with Fluoro-Gold, a marker of retrograde transport from transected fibres, or by immunoreactivity for c-jun protein, an indicator of injury and regeneration, suggested that many of the neurones expressing alpha2A-AR-IR were uninjured by the sciatic lesions. 4. In general the largest proportionate increase in numbers of neurones labelled by alpha2A-AR-IR after nerve lesions appeared in the medium-large diameter range (31-40 microm), a group principally composed of cell bodies of low threshold mechanoreceptors. The number of small diameter DRG neurones labelled by alpha2A-AR-IR, a category likely to include somata of nociceptors, also increased but proportionately less. 5. Relatively few DRG neurones exhibited alpha2C-AR-IR; this population did not appear to change after either nerve lesions or inflammation. 6. These observations are considered in relation to effects of nerve injury on excitation of primary afferent neurones by sympathetic activity or adrenergic agents, sympathetically related neuropathy and reports of sprouting of sympathetic fibres in DRG.
1. The effects of impulse activity on conduction in cutaneous C fibres have been examined in 46 microneurographic recordings from 11 normal subjects and 11 diabetic patients with normal nerve conduction. A tungsten microelectrode was inserted into a cutaneous nerve, usually the superficial peroneal close to the ankle, and intraneural microstimulation was used to identify an area of skin innervated. Three minute trains of 0.25 ms stimuli at 1, 2 and 4 Hz were then delivered to the surface of the skin, separated by intervals of 6 min with stimulation at 0.25 Hz. Slowing and block of conduction were measured from the nerve responses for up to seven C units per stimulation sequence. 2. Three types of C unit were distinguished by their responses to repetitive stimulation: type 1 units slowed progressively during the 3 min trains; slowing of type 2 units reached a plateau within 1 min; while type 3 units hardly slowed at all. Data from normal and diabetic subjects did not differ and were pooled. After 3 min at 2 Hz, the percentage increases in latency were for type 1, 28.3 +/- 9.7 (n = 63 units, mean +/- s.d.); for type 2, 5.2 +/- 1.6 (n = 14); and for type 3, 0.8 +/- 0.5 (n = 5), with no overlap. After 3 min at 4 Hz, 58 % of type 1 units (but no type 2 or 3 units) blocked intermittently. Recovery of latency after stimulation was faster for type 2 than for type 1 units, but conduction velocities of the three types were similar. 3. Type 1 units were identified as nociceptors and 7 type 2 units were identified as 'cold' fibres, activated by non-noxious cold, with no overlap in modality. None of the units tested was activated by weak mechanical stimuli or reflex sympathetic activation. 4. Spike waveforms were averaged for 18 type 1, 10 type 2 and 6 type 3 units. All units had predominantly triphasic action potentials with a major negative peak, but those of type 3 units were on average both smaller and briefer than those of type 1 and type 2 units. 5. It is concluded that repetitive electrical stimulation reliably differentiates nociceptive from cold-specific C fibres innervating human hairy skin, as has previously been shown for the rat. Cold fibres can propagate impulses continuously at much higher rates than nociceptive fibres. The nature of the type 3 units is unclear.
Painful nerve and tissue injuries can be exacerbated by activity in sympathetic neurons. The mechanisms of sympathetically maintained pain (SMP) are unclear.
To determine the effect of cutaneous sympathetic activity on pain induced by primary afferent C-nociceptor sensitization with capsaicin in humans.
In healthy volunteers capsaicin was applied topically (n = 12) or injected into the forearm skin (n = 10) to induce spontaneous pain, dynamic and punctate mechanical hyperalgesia, and antidromic (axon reflex) vasodilatation (flare). Intensity of pain and hyperalgesia, axon reflex vasodilatation (laser Doppler), and flare size and area of hyperalgesia (planimetry) were assessed. The local skin temperature at the application and measurement sites was kept constant at 35 degrees C. In each individual the analyses were performed during the presence of high and low sympathetic skin activity induced by whole-body cooling and warming with a thermal suit. By this method sympathetic vasoconstrictor activity is modulated in the widest range that can be achieved physiologically. The degree of vasoconstrictor discharge was monitored by measuring skin blood flow (laser Doppler) and temperature (infrared thermometry) at the index finger.
The intensity and spatial distribution of capsaicin-evoked spontaneous pain and dynamic and punctate mechanical hyperalgesia were identical during the presence of high and low sympathetic discharge. Antidromic vasodilatation and flare size were significantly diminished when sympathetic vasoconstrictor neurons were excited.
Cutaneous sympathetic vasoconstrictor activity does not influence spontaneous pain and mechanical hyperalgesia after capsaicin-induced C-nociceptor sensitization. When using physiologic stimulation of sympathetic activity, the capsaicin model is not useful for elucidating mechanisms of SMP. In neuropathic pain states with SMP, different mechanisms may be present.
Patients with reflex sympathetic dystrophy have posttraumatic pain disproportionate to the injury and spreading beyond the distribution of any single peripheral nerve. We examined sympathetic neurocirculatory function and the role of sympathetic postganglionic nerve traffic in maintaining the pain in 30 patients with reflex sympathetic dystrophy. Most had had the condition for more than 1 year, and 14 had undergone sympathectomy for the pain. Positron emission tomographic scanning after administration of 13N-ammonia was used to assess local perfusion, and 6-[18F]fluorodopamine was used to assess sympathetic innervation. Rates of entry of norepinephrine in the regional venous drainage (spillovers) and regional plasma levels of L-dihydroxyphenylalanine (the immediate product of the rate-limiting enzymatic step in norepinephrine biosynthesis) and dihydroxyphenylglycol (the main neuronal metabolite of norepinephrine) were measured with and without intravenous trimethaphan for ganglion blockade. 13N-Ammonia-derived radioactivity was less on the affected side than on the unaffected side, whereas 6-[18F]fluorodopamine-derived radioactivity was symmetrical. Thus, perfusion-adjusted 6-[18F]fluorodopamine-derived radioactivity was higher on the affected side. Norepinephrine spillover and arteriovenous increments in plasma levels of L-dihydroxyphenylalanine and dihydroxyphenylglycol did not differ significantly between affected and unaffected limbs, although 4 patients had noticeably less norepinephrine spillover and smaller arteriovenous increments in plasma dihydroxyphenylglycol on the affected side. Trimethaphan decreased the pain in only 2 of 12 nonsympathectomized patients. The results indicate that patients with chronic unilateral reflex sympathetic dystrophy have decreased perfusion of the affected limb, symmetrical sympathetic innervation and norepinephrine synthesis, variably decreased release and turnover of norepinephrine in the affected limb, and failure of ganglion blockade to improve the pain in most cases. These findings suggest augmented vasoconstriction, intact sympathetic terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows.
Tissue injuries, with or without involvement of nerves, may lead to ongoing pain and hyperalgesia to external stimuli. In a subset of patients, the pain is maintained by sympathetic efferent activity (SMP). We investigated if the peripheral administration of the alpha-adrenergic agonist, norepinephrine (NE), in physiologically relevant doses resulted in pain in patients with SMP. To establish the dose of intradermal NE required to induce cutaneous vasoconstriction, NE (1 nM-10 microM, 30 microl) was injected under a laser Doppler probe on the volar forearm of seven normal subjects. A decrease in blood flow was evident at a dose of 10 microM. Twelve patients (five male, seven female) diagnosed to have SMP based on the decrease in pain by a local anesthetic sympathetic blockade (70+/-6%) were enrolled in the study. Pain ratings were obtained continuously for 5 min after intradermal injections of saline and NE (0.1-10 microM) into their hyperalgesic zone and the mirror-image contralateral side. Injections were done during the period of pain relief following a local anesthetic sympathetic blockade. Similar injections were made in eight control subjects. On the affected side of the patients, the two highest concentrations of NE (1 and 10 microM) caused significantly more pain than saline (P<0.05, ANOVA). In contrast, there was no significant pain induced by the NE injections in the unaffected side and in control subjects. Six of nine patients tested reported a marked decrease in pain and hyperalgesia following infusion of phentolamine (1 mg/kg over 10 min). Two of the three patients who did not receive pain relief following phentolamine infusion also did not report pain to the NE injections. We conclude that NE injections produce pain in SMP patients at doses that are at the threshold for producing vasoconstriction. These studies support a role for cutaneous adrenoceptors in the mechanisms of sympathetically maintained pain.
In simultaneous bilateral nerve recordings, patients with Sympathetically Maintained Pain (SMP) affecting one limb show similar sympathetic traffic in nerves supplying the affected and unaffected limb, also when the painful limb shows a marked regional autonomic (vasomotor) dysfunction. These findings argue against the notion that SMP must be mediated by a reflex change in the pattern of sympathetic discharge. In general, they underline the fact that autonomic effector disturbances may give little information about underlying nerve traffic.
We have examined the effect of an intradermal injection of phenylephrine (1mg/0.1 ml), an alpha-1-adrenoceptor agonist in normal subjects, and patients with sympathetically-independent (SIP) and sympathetically-maintained pain (SMP). Normal subjects and SIP patients experienced only brief stinging pain, while subsets of both sympathectomized and non-sympathectomized SMP patients (6/9 and 4/8, respectively) experienced an additional abnormal pain response accompanied by mechano-allodynia around the injection site. Both the normal and abnormal pain response after intradermal phenylephrine are similar to those observed with intradermal norepinephrine. In contrast to previous reports in the literature, we found that three sympathectomized SMP patients (who, however, had failed to experience pain relief after surgical sympathectomy despite very good relief after sympathetic blocks) also experienced abnormal pain and mechano-allodynia when phenylephrine was injected to a limb contralateral to the symptomatic sympathectomized extremity. Abnormal pain response evoked by norepinephrine or phenylephrine injection in the ipsilateral symptomatic limb of SMP patients may be due to injury-evoked nociceptor responsiveness to catecholamines. However, such a response in contralateral asymptomatic limbs suggests an additional factor that more likely than not is of central origin and may or may not be related to sympathectomy and its success or failure to treat pain.
To describe and identify the function of a class of human C fibre with an unusual response to repetitive electrical stimulation. Other C fibres slow progressively at 2 Hz (type 1), reach a latency plateau (type 2) or hardly slow at all (type 3).
C fibres innervating hairy skin were recorded by microneurography in the superficial peroneal nerves of 19 healthy volunteers. Baseline electrical stimulation of the skin was at 0.25 Hz, and activity-dependent slowing recorded during stimulation at 2 Hz for 3 min and after a 3-min pause in stimulation.
In 41 units, there was a partial recovery of latency during repetitive stimulation. These were classified as 'type-4' units, and identified as sympathetic efferents, since they exhibited spontaneously activity, which was enhanced by manoeuvres that increase sympathetic outflow (15 of 16 cases) and/or suppressed by a proximal anaesthetic block (eight of eight cases). The peak slowing during 2 Hz trains averaged 6.47 +/- 2.06% (mean +/- SD, n=41), but after 3 min the slowing had reduced to 4.90 +/- 2.20%, which was less than in all type 1 (nociceptor) fibres but similar to that in type 2 (cold) fibres. Compared with cold fibres, type-4 sympathetic fibres slowed more after the first 10 impulses at 2 Hz (2.57 +/- 0.45%) and also after a pause in stimulation (1.66 +/- 0.51%).
The distinctive activity-dependent slowing profiles of these type-4 sympathetic C units may help identification in vitro, and suggest that hyperpolarization-activated channels have a particularly prominent role in the axonal membrane.
Sympathetically maintained pain could either be mediated by ephaptic interactions between sympathetic efferent and afferent nociceptive fibers or by catecholamine-induced activation of nociceptive nerve endings. We report here single fiber recordings from C nociceptors in a patient with sympathetically maintained pain, in whom sympathetic blockade had repeatedly eliminated the ongoing pain in both legs. We classified eight C-fibers as mechano-responsive and six as mechano-insensitive nociceptors according to their mechanical responsiveness and activity-dependent slowing of conduction velocity (latency increase of 0.5+/-1.1 vs. 7.1+/-2.0 ms for 20 pulses at 0.125 Hz). Two C-fibers were activated with a delay of several seconds following strong endogenous sympathetic bursts; they were also excited for about 3 min following the injection of norepinephrine (10 microl, 0.05%) into their innervation territory. In these two fibers, a prolonged activation by injection of low pH solution (phosphate buffer, pH 6.0, 10 microl) and sensitization of their heat response following prostaglandin E2 injection were recorded, evidencing their afferent nature. Moreover, their activity-dependent slowing was typical for mechano-insensitive nociceptors. We conclude that sensitized mechano-insensitive nociceptors can be activated by endogenously released catecholamines and thereby may contribute to sympathetically maintained pain. No evidence for ephaptic interaction between sympathetic efferent and nociceptive afferent fibers was found.
In diseases such as complex regional pain syndrome (CRPS), where neuropathic pain is the primary concern, traditional pain classifications and lesion descriptors are of limited value. To obtain better treatment outcomes for patients, the underlying pathophysiological mechanisms of neuropathic pain need to be elucidated and analysed so that therapeutic targets can be identified and specific treatments developed.
In the present review, we examine the current literature on sympathetically maintained pain (SMP), a subset of neuropathic pain, within the context of CRPS. Evidence from both human and animal studies is presented and discussed in terms of its support for the existence of SMP and the mechanistic information it provides.
We discuss three current hypotheses that propose both a site and method for sympathetic–sensory coupling: (i) direct coupling between sympathetic and sensory neurons in the dorsal root ganglion; (ii) chemical coupling between sympathetic and nociceptive neuron terminals in skin; and (iii) the development of a‐adrenoceptor‐mediated supersensitivity in nociceptive fibres in skin in association with the release of inflammatory mediators.
Finally, we propose a new hypothesis that integrates the mechanisms of chemical coupling and a‐adrenoceptor‐mediated supersensitivity. This hypothesis is based on previously unpublished data from our laboratory showing that a histological substrate suitable for sympathetic–sensory coupling exists in normal subjects. In the diseased state, the nociceptive fibres implicated in this substrate may be activated by both endogenous and exogenous noradrenaline. The mediating a‐adrenoceptors may be expressed on the nociceptive fibres or on closely associated support cells.