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Review series
The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010 3779
Central modulation of pain
Michael H. Ossipov, Gregory O. Dussor, and Frank Porreca
Department of Pharmacology, University of Arizona, Tucson, Arizona, USA.
It has long been appreciated that the experience of pain is highly variable between individuals. Pain results from
activation of sensory receptors specialized to detect actual or impending tissue damage (i.e., nociceptors). However,
a direct correlation between activation of nociceptors and the sensory experience of pain is not always apparent.
Even in cases in which the severity of injury appears similar, individual pain experiences may vary dramatically.
Emotional state, degree of anxiety, attention and distraction, past experiences, memories, and many other factors
can either enhance or diminish the pain experience. Here, we review evidence for “top-down” modulatory circuits
that profoundly change the sensory experience of pain.
Existence of an endogenous pain inhibitory system
Early evidence for pain modulatory mechanisms came from obser-
vations of H.K. Beecher, who noted a remarkable attenuation of
pain experienced by soldiers in combat situations (1). Analogous
observations have been seen in others, including athletes that con-
tinue competition despite significant injuries (see ref. 2). Beecher, a
physician who served with the US Army during the Second World
War, observed that as many as three-quarters of badly wounded
soldiers reported no to moderate pain and did not want pain relief
medication (1). This observation was striking, because the wounds
were not trivial but consisted of compound fractures of long bones
or penetrating wounds of the abdomen, thorax, or cranium. More-
over, only individuals who were clearly alert, responsive, and not
in shock were included in his report (1), leading to the conclusion
that “strong emotions” block pain (1).
The existence of endogenous mechanisms that diminish pain
through net “inhibition” is now generally accepted. Pain modu-
lation likely exists in the form of a descending pain modulatory
circuit with inputs that arise in multiple areas, including the hypo-
thalamus, the amygdala, and the rostral anterior cingulate cortex
(rACC), feeding to the midbrain periaqueductal gray region (PAG),
and with outputs from the PAG to the medulla. Neurons within
the nucleus raphe magnus and nucleus reticularis gigantocellu-
laris, which are included within the rostral ventromedial medulla
(RVM), have been shown to project to the spinal or medullary dor-
sal horns to directly or indirectly enhance or diminish nocicep-
tive traffic, changing the experience of pain (3). This descending
modulatory circuit is an “opioid-sensitive” circuit (see below) and
relevant to human experience in many settings, including in states
of chronic pain, and in the actions of pain-relieving drugs, includ-
ing opiates, cannabinoids, NSAIDs, and serotonin/norepineph-
rine reuptake blockers that mimic, in part, the actions of opiates
(Figure 1). While the precise mechanisms by which drugs produce
pain relief is not entirely understood, strong evidence supports the
actions of these drugs through the pain modulatory circuit or by
mimicking the consequence of activation of this descending cir-
cuit at the level of the spinal cord.
“Top-down” modulatory pathways have been shown to under-
lie the robust and clinically important phenomenon of placebo
analgesia, which can be demonstrated in approximately one-third
of the population (4). Patients that had undergone removal of
impacted molars and who were expecting an analgesic showed
reduced pain scores after placebo injection (5). Placebo respond-
ers that blindly received the opiate antagonist naloxone indicated
pain levels similar to those of the nonresponders, indicating that
placebo analgesia required activation of endogenous opioid-medi-
ated inhibition (5). Neuroimaging techniques have now estab-
lished that the placebo response is likely mediated by activation
of pain inhibitory systems, originating from cortical and subcorti-
cal regions (6, 7). Human imaging studies with [11C]-carfentanil
revealed that placebo analgesia was related to activation of μ-opi-
oid receptors in the rACC, the pregenual cingulate cortex (pCC),
the dorsolateral prefrontal cortex, and the anterior insular cortex
(7). Changes in regional blood flow revealed that expectation of
placebo analgesia activated a neural network from the rACC to
include subcortical regions known to be active in opioid-mediated
antinociception, such as the PAG (6). Increased regional cerebral
blood flow to these sites was associated with a greater placebo
response, leading to the suggestion that individual variations in
placebo responses may be linked to differences in either concentra-
tion or function of μ-opioid receptors (6).
Imaging studies have led to the suggestion of a “pain matrix,”
brain areas that are consistently activated by noxious stimuli.
These areas often include, but are not restricted to, the rACC,
pCC, somatosensory cortex 1 and 2, the insula, amygdala and
thalamus, and the PAG (8). Interestingly, these regions demon-
strate overlap among brain sites activated by opioids and those
that are activated by placebo analgesia, and imaging studies sug-
gest that coupling between the rACC and the PAG is mediated
through endogenous opioidergic signaling and is essential to
both opioid-induced analgesia and placebo-mediated analgesia
(9). It should be noted that the concept of a pain matrix is not
meant to suggest a rigid regulatory pathway but rather concep-
tually represents a collection of brain regions that are involved
in neurological functions, including cognition, emotion, moti-
vation, and sensation as well as pain. These regions, acting
together in the context of modulation of nociception, appear to
give rise to the experience of pain (10). It is noted that analgesic
drugs as well as expectation, distraction, emotional context, and
other factors engage several nodes of the pain matrix to change
the pain experience.
Engagement of descending modulation can facilitate, as well as
inhibit, pain. The term “nocebo” has been introduced to describe
an effect opposite to that of the placebo, indicated by expectation
of a worsening outcome in response to a treatment (11). For exam-
ple, patients who were expecting pain relief with a NSAID and
were then told they were to receive a drug that was hyperalgesic
Conflict of interest: The authors have declared that no conflict of interest exists.
Citation for this article: J Clin Invest. 2010;120(11):3779–3787. doi:10.1172/JCI43766.
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3780 The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010
responded with enhanced pain (12). When subjects were told ver-
bally, nonverbally through the application of conditioning stim-
uli, or both ways that enhanced pain was to be expected, it was
found that expectation of pain resulted in pain to nonpainful
stimuli as well as enhanced pain in response to noxious stimuli
(13). In order to isolate the effect of expectancy in an imaging
study, subjects were presented with visual cues indicating that
either a high or low noxious thermal stimulus would be applied
but then were actually presented with the high stimulus (14).
This procedure revealed changes in the ipsilateral caudal ACC,
the head of the caudate, the cerebellum, and the contralateral
cuneiform nucleus (nCF), suggesting that increased pain expec-
tancy activates a pain network that modulates afferent input at
the level of the nCF (14).
Neuroanatomical and electrophysiological evidence
of endogenous pain inhibition
Although the existence of pain modulatory systems had been sur-
mised for many decades, it was not until electrical stimulation or
microinjection of opiates into specific brain regions that the impor-
tance and clinical significance of such systems was appreciated. In
what may have been the first demonstration of a brain site-specific
action for the antinociceptive effect of morphine, Tsou and Jang
surmised that since morphine blocks pain at doses that do not
affect other sensory modalities, it was likely working through a site
specific for pain control. Thus, they microinjected morphine into
several regions of the rabbit brain and discovered that a profound
antinociceptive effect occurred only when morphine was applied
into the PAG (15). Reynolds found that electrical stimulation of the
ventrolateral PAG of the rat produced an antinociception so power-
ful that a laparotomy could be performed in a fully conscious rat,
without observable signs of distress to the animal (16).
Electrical stimulation of the PAG was rapidly adapted to humans
in efforts to relieve intractable pain (17–19). While PAG stimulation
has been largely discontinued because of side effects, such as anxiety,
distress, and, in some instances, development of migraine-like head-
ache (20), deep brain stimulation aimed at other regions remains an
approach that might control otherwise intractable pain (21). Criti-
cally, the reversal of intractable pain by stimulation of the PAG was
blocked by naloxone, indicating the activation of an endogenous
opioidergic pain inhibitory system (17). These early studies were
not rigorous, placebo-controlled double-blind trials, and, as a con-
sequence, the possibility of placebo analgesia cannot be disregarded.
Even so, the existence of a placebo effect, as discussed above, is likely
dependent on activation of pain modulatory circuits.
Preclinical studies have attempted to delineate the sites and
pathways that compose the endogenous pain inhibitory circuit.
Considerable overlap has been found between sites that produce
antinociception with either electrical stimulation or morphine
Figure 1
Schematic representation of pain modularity circuitry. Nociceptive
inputs enter the spinal dorsal horn through primary afferent fibers that
synapse onto transmission neurons. The projection fibers ascend
through the contralateral spinothalamic tract. Ascending projections
target the thalamus, and collateral projections also target mesence-
phalic nuclei, including the DRt, the RVM, and the midbrain PAG.
Descending projections from the DRt are a critical component of the
DNIC pathway. Rostral projections from the thalamus target areas that
include cortical sites and the amygdala. The lateral capsular part of
the CeA (“nociceptive amygdala”) receives nociceptive inputs from the
brainstem and spinal cord. Inputs from the thalamus and cortex enter
through the lateral (LA) and basolateral (BLA) amygdala. The CeA
sends outputs to cortical sites and the thalamus, in which cognitive and
conscious perceptions of pain are integrated. Descending pain modu-
lation is mediated through projections to the PAG, which also receives
inputs from other sites, including the hypothalamus (data not shown),
and communicates with the RVM as well as other medullary nuclei that
send descending projections to the spinal dorsal horn through the DLF.
The noradrenergic locus coeruleus (LC) receives inputs from the PAG,
communicates with the RVM, and sends descending noradrenergic
inhibitory projections to the spinal cord. Antinociceptive and prono-
ciceptive spinopetal projections from the RVM positively and nega-
tively modulate nociceptive inputs and provide for an endogenous pain
regulatory system. Ascending (red) and descending (green) tracts are
shown schematically. Areas labeled “i–iv” in the small diagram cor-
respond with labeled details of the larger diagram.
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The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010 3781
microinjection (22–26). Both stimulation-produced antinocicep-
tion (SPA) and antinociception from morphine microinjection
into supraspinal loci are reversed by naloxone, further implicating
the activation of endogenous opioidergic systems in these phe-
nomena (27). These studies have revealed descending pain inhibi-
tory projections to the level of the spinal cord, either directly or
indirectly from the PAG. Surgical disruption of the dorsolateral
funiculus (DLF) abolished supraspinally mediated antinociception
(26), and anterograde and retrograde tracing studies revealed that
the RVM sends spinopetal projections through this tract (28–30).
The precise site of projection of these fibers and their role in inhi-
bition or facilitation remains unclear.
The amygdala in descending modulation
Human imaging studies reveal connections linking the PAG to
the amygdala and cortical sites (2, 31). These studies suggest that
interactions between the prefrontal cortex and the amygdala pro-
vide emotional-affective modulation of cognitive functions in
pain, driving tasks such as decision making, assessment of risk/
reward versus pain, or punishment avoidance (32). The amygdala
plays important roles in emotional responses, stress, and anxiety
and is believed to be a critical component of the pain matrix. This
region may contribute significantly to the integration of pain and
associated responses such as fear and anxiety.
Electrophysiological studies in animals demonstrated that neu-
rons of the central nucleus of the amygdala (CeA) showed exci-
tation with noxious stimulation of the knee joint or deep tissue
(33) and enhanced responses after peripheral (34) or visceral (35)
inflammation. Sensitization of CeA neurons, mediated through
metabotropic glutamate receptors, represents neuroplastic chang-
es that appear to promote chronic pain (36, 37). Administration
of a corticotropin-releasing factor (CRF1) receptor antagonist
into the CeA of rats inhibited both nociceptive responses as well
as anxiety-like behaviors (38). Hemispheric lateralization of the
role of the amygdala in pain processing has been recently dem-
onstrated, since, although both the left and right CeA showed
responses to brief noxious stimuli, only the right CeA respond-
ed with enhancement of firing and increased receptive field size
after either ipsilateral or contralateral peripheral inflammation
(39). Moreover, peripheral inflammation produced activation of
extracellular signal-regulated kinase cascade only in the right CeA,
regardless of site of inflammation (40), and blockade of activity of
this kinase in the right CeA, but not the left CeA, blocked behav-
ioral signs of enhanced inflammatory pain (40).
The RVM and descending modulation: ON and OFF cells
Electrophysiologic studies and lesioning experiments have revealed
that the RVM receives neuronal inputs from the PAG and is likely
to be the final common relay in descending inhibition of noci-
ception from supraspinal sites (41). The microinjection of lido-
caine into the RVM abolished antinociception arising from elec-
trical stimulation of the PAG (42). Descending projections from
the RVM course through the DLF to the spinal dorsal horn and
form synaptic connections with primary afferent terminals and
second- and third-order neurons that transmit nociceptive signals
to supraspinal sites as well as with interneurons and thus are well
situated to modulate nociceptive inputs (43–45).
Important insights into the nature of descending modulatory cir-
cuitry came from studies by Fields and colleagues, in which activity
of neurons in the RVM were paired with a behavior elicited by a nox-
ious stimulus (i.e., the tail-flick response to noxious heat) in lightly
anesthetized rats (41, 46, 47). These studies led to the identification
of a population of RVM neurons that increase firing just prior to
the initiation of the nociceptive reflex (i.e., “on-cells”), and another
population of neurons was found to decrease firing just prior to the
tail-flick (i.e., “off-cells”) (48–50). Activity of other “neutral” cells did
not correlate with nociceptive stimuli. Both the off-cells and on-cells
were found to project to the spinal dorsal horn, indicating that they
may exert modulatory influences on nociceptive inputs (51–52).
This dichotomy in neuronal function is consistent with bidirec-
tional pain modulation. Studies performed with electrical stimula-
tion or microinjection of glutamate into the RVM revealed a bipha-
sic function of the RVM, with regard to pain modulation (53–56).
Low intensities of stimulation inhibited nociceptive responses,
whereas higher levels of stimulation enhanced nociception (53–57).
This biphasic role of the RVM in pain modulation was shown with
electrophysiologic responses of spinal cord neurons or with behav-
ioral responses and occurred with either cutaneous or visceral
stimuli (53–57). The electrophysiologic characteristics of the on-
cells are consistent with a pronociceptive function. For example,
prolonged delivery of a noxious thermal stimulus increased the
firing rate of RVM on-cells as well as enhanced the intensity of
the nociceptive response in rats (58). Both enhanced nociceptive
responses and increased on-cell activity were abolished by lido-
caine microinjected into the RVM (58). Hyperalgesia caused by nal-
oxone-precipitated withdrawal was accompanied by increased on-
cell activity (59). Finally, the subdermal injection of formalin into
a hind paw of a rat produced exaggerated behavioral responses as
well as increased responses of on-cells of the RVM (60).
The activation of descending inhibitory pathways that project to
the spinal and medullary dorsal horns has led to the question of
the nature of these projections. Opioids administered systemically
or into the PAG result in increased activity of off-cells through
disinhibition, and it is believed that activation of off-cells is “nec-
essary and sufficient” for analgesia (61–63). In contrast, the on-
cells are the only population of cells in the RVM directly inhibited
by opioids, suggesting that these cells likely express the μ-opioid
receptors (64). These cells are also activated by cholecystokinin
(CCK) via a CCK2 receptor (48, 64, 65). Neuroanatomical stud-
ies reported a high degree of colocalization of CCK2 receptors
with μ-opioid receptors on RVM neurons, presumed to be pain
facilitation cells that may correspond with on-cells (66). Addition-
ally, most (i.e., >60%) off-cells, on-cells, and neutral cells have been
shown to express glutamate decarboxylase (67). However, the role
of GABA in the function of these cells remains unclear.
Descending serotonergic pathways
Early studies with available serotonergic antagonists blocked
SPA initiated from the RVM (68), leading to the suggestion that
descending inhibition of pain was mediated through serotonergic
neurons projecting from the RVM through the DLF (29). Stimula-
tion of the PAG or RVM was found to cause release of serotonin
in the spinal cord (69), and intrathecal administration of 5-HT
agonists elicited antinociception (70), whereas intrathecal 5-HT
antagonists attenuated SPA from the RVM (71). Retrograde label-
ing studies demonstrated the presence of serotonergic projections
to the spinal dorsal horn arising from the nucleus raphe magnus,
which is a midline structure within the RVM as well as the nucle-
us paragigantocellularis and the ventral portion of the nucleus
gigantocellularis (72). Together, such studies led to the reason-
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3782 The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010
able assumption that the RVM provided descending serotonergic
pain modulation from the RVM. However, attempts to determine
whether either the on-cells or off-cells of the RVM are serotonergic
led to the realization that other, nonserotonergic neurons from
the RVM may modulate pain (73). In a study of 25 identified RVM
neurons, none of the on-cells (i.e., 8 neurons) or off-cells (i.e.,
9 neurons) expressed 5-HT, and only 4 out of 8 neutral cells were
labeled with 5-HT (73). Moreover, only 20% of RVM neurons were
found to be serotonergic (74), and most of the spinal projections
from the RVM are either glycinergic or GABAergic. It has been
argued that serotonergic RVM neurons are neither on-cells nor off-
cells but that they can modulate the activities of these neurons (see
refs. 75 and 76). However, a recent study, in which descending sero-
tonergic RVM neurons were selectively ablated through the use of
shRNA plasmids and electroporation, demonstrated that descend-
ing serotonergic projections from the RVM are important for facili-
tation of pain in inflammatory or neuropathic pain states, although
they are not necessary for opioid-mediated inhibition of acute
pain (77). Electrophysiologic studies suggested that GABAergic
and glycinergic projections from the RVM mediate antinocicep-
tion. In addition to the descending serotonergic populations that
are activated, the diversity of subtypes of the 5-HT receptors and
the complex anatomy of the spinal dorsal horn complicates inter-
pretation of the role of serotonin in pain modulation.
The effect of spinal serotonin can be either inhibitory or facilita-
tory, depending on the receptor subtype activated (78–82). Spinal
administration of an antagonist of the inhibitory 5-HT7 receptor
blocked the antinociceptive effect of morphine microinjected into
the RVM, whereas pharmacological antagonism of the facilitatory
5-HT3 receptor blocked hyperalgesia induced by CCK adminis-
tered into the RVM (79). Further, systemic administration of
5-HT7 agonists blocked capsaicin-induced hyperalgesia in mice,
whereas 5-HT7 antagonists elicited mechanical hypersensitivity
(83). The 5-HT7 receptor has been identified in the dorsal root
ganglion and on central terminals of primary afferent fibers
(84, 85) as well as on GABAergic interneurons in the dorsal horn
of the spinal cord (84), which is consistent with a role in pain
modulation (83). Although these observations indicate an impor-
tant serotonergic role for pain modulation, the precise spinal
mechanisms involved remain unclear.
Noradrenergic systems and pain modulation
Electrical stimulation of the PAG or RVM to elicit antinociception
increases measured norepinephrine levels in the cerebrospinal fluid,
and this effect was blocked by spinal adrenergic antagonists (69, 86–88).
These findings suggest a strong contribution of norepinephrine in
antinociception associated with descending inhibition. While nei-
ther the PAG nor the RVM contain noradrenergic neurons, both
regions communicate with noradrenergic sites important to pain
modulation, including the A5 (locus coeruleus), A6, and A7 (Köl-
liker-Füse) nuclei (89–91). These noradrenergic nuclei are a major
source of direct noradrenergic projections to the spinal cord (3, 92)
and likely may serve to ultimately inhibit the response of presynap-
tic and postsynaptic spinal pain transmission neurons (3, 92).
Numerous studies have demonstrated that activation of spinal
α2-adrenergic receptors exerts a strong antinociceptive effect (93–95).
Spinal clonidine blocked thermal and capsaicin-induced pain in
healthy human volunteers (96). PAG activation resulted in inhibition
of the nociceptive responses of dorsal neurons mediated through
activation of spinal α2 receptors (97). Activation of α2-adrenergic
receptors has been shown to inhibit nociceptive transmission at
the level of the spinal cord through presynaptic activity, inhibiting
release of excitatory neurotransmitters from primary afferent ter-
minals, as well as through postsynaptic sites (93). Recordings per-
formed on spinal cord slices revealed that activation of α2-adrenergic
receptors hyperpolarized neurons and was thus inhibitory. Recently,
it has also been demonstrated that activation of α1-adrenergic recep-
tors caused depolarization of GABA interneurons (98), demonstrat-
ing an additional mechanism of enhancing inhibition. Activation
of spinal α1-adrenergic receptors also enhances responses of dorsal
horn neurons to noxious inputs (97).
Descending modulation and stress-induced analgesia
The mechanisms mediating the suppression of pain by stress have
been intensively studied. Watkins and colleagues (99) found that
stress induced by brief foot shock of the forepaws of rats pro-
duced antinociception as measured in the tail-flick test. Lesions
of the DLF made rostral to the entry zone of the peripheral nerves
of the forelimbs, which kept intact any direct spinal communica-
tions between forelimb and tail, abolished stress-induced analge-
sia (SIA), indicating that supraspinal sites were necessary to acti-
vate a spinopetal pain inhibitory circuit (99). Additionally, it was
found that antinociception induced by brief shock of the fore-
paws was abolished by systemic and intrathecal naloxone, indi-
cating the activation of endogenous opioidergic pain inhibitory
systems (99). Stress induced by foot shock reduced firing of RVM
on-cells and increased that of off-cells, consistent with opioider-
gic endogenous pain modulatory systems (100). SIA is associated
with elevated PAG levels of β-endorphin (101), and microinjection
of μ-opioid receptor antagonists into the PAG or RVM abolished
SIA (102–104). Opioid microinjection into the amygdala elicits
antinociception that is blocked by lidocaine in either the PAG or
RVM (105). These and other studies led to the conclusion that SIA
can be opioid sensitive and mediated through descending inhibi-
tory pathways from amygdala, the PAG, and through RVM projec-
tions to the spinal cord (106).
However, preclinical studies have also revealed that some aspects
of SIA are not sensitive to naloxone and therefore are likely to be
mediated via different mechanisms. Recent studies have revealed a
role of endogenous cannabinoids in SIA and in descending modu-
latory pathways. Inhibition of RVM activity by microinjection of
muscimol abolished antinociception induced by systemic injec-
tion of the cannabinoid agonist WIN55,212-2 (107). Moreover,
WIN55,212-2 increased RVM off-cell activity and reduced firing
of the RVM on-cells, analogous to the effect of morphine, but
these effects were not blocked by naloxone, indicating that these
effects are mediated specifically through cannabinoid receptors
(107). Studies with a CB1 antagonist revealed that tonic release of
endogenous cannabinoids increases off-cell activity and diminish-
es on-cell firing and may modulate baseline nociceptive thresholds
through regulation of RVM activity (107), mechanisms that could
also underlie opioid-insensitive SIA. Opioid-insensitive SIA was
abolished by systemic administration of CB1, but not CB2, antag-
onists (108). Microinjection of the CB1 antagonist rimonabant
into the dorsolateral PAG abolished such antinociception, further
suggesting that SIA is mediated by endogenous cannabinoids
(108). Opioid-insensitive SIA was associated with elevated levels
of endogenous cannabinoids in the PAG, and SIA was enhanced
by microinjection of inhibitors of monoacylglycerol lipase, which
hydrolyzes the endogenous cannabinoid 2-arachidonoylglycerol
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The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010 3783
(108). Finally, microinjection of a CB1 antagonist into the RVM
blocked SIA, whereas inhibition of hydrolysis of endogenous can-
nabinoids in the RVM enhanced SIA (109). These studies indicate
that endogenous cannabinoids, like opioids, regulate pain sensitiv-
ity in response to environmental conditions through descending
pathways (109). As SIA produces many generalized effects, includ-
ing release of stress hormones, multiple physiological actions
result that may contribute to antinociceptive effects and to pain.
Descending facilitation and experimental chronic pain
Increased descending facilitation in experimental chronic pain mod-
els has been demonstrated; but, to date, how this mechanism par-
ticipates in clinical conditions has not been determined. Emerging
preclinical evidence suggests that activation of putative pain facili-
tation cells maintains descending facilitation and promotes neuro-
pathic pain. The microinjection of lidocaine into the RVM of rats
with peripheral nerve injury abolished behavioral signs of enhanced
abnormal pain (110–112). Moreover, the surgical disruption of
the DLF ipsilateral but not contralateral to nerve injury abolished
behavioral signs of enhanced abnormal pain but did not alter nor-
mal responses in sham-operated animals (111, 113). Microinjection
of CCK into the RVM produced behavioral evidence of enhanced
nociception that was blocked by lesion of the DLF (112, 114) and
markedly increased on-cell activity (115). Accordingly, microin-
jection of the CCK2 antagonist, L365,260, into the RVM reversed
behavioral signs of neuropathic pain in nerve-injured rats (112).
Microinjection of the potent μ-opioid agonist dermorphin, con-
jugated to the ribosome-inactivating protein saporin, to rats with
peripheral nerve injury produced a selective knockdown of RVM
neurons that express the μ-opioid receptor, along with a rever-
sal of behavioral signs of neuropathic pain (111, 116). Addition-
ally, the selective knockdown of CCK2-expressing neurons using
CCK-saporin resulted in a substantial reduction in RVM neurons
expressing the μ-opioid receptor, whereas the knockdown of RVM
neurons expressing μ-opioid receptors with the dermorphin-sapo-
rin conjugate resulted in a substantial reduction in numbers of
neurons expressing CCK2 (66). Both of these manipulations abol-
ished behavioral and neurochemical signs of neuropathic pain in
rats with spinal nerve ligation (66). Furthermore, a recent study
demonstrated that blockade of RVM activity by microinjection of
lidocaine elicited reward in models of neuropathic pain, suggest-
ing that descending facilitation also likely contributes to tonic-
aversive (i.e., stimulus-independent) aspects of such pain (117).
Activation of descending facilitation after peripheral nerve
injury has been associated with pronociceptive changes in the spi-
nal cord. Peripheral nerve injury resulted in enhanced capsaicin-
evoked release of CGRP from primary afferent fibers in spinal cord
sections and upregulation of spinal dynorphin to pathological
levels (111, 118, 119). Manipulations that abolished descending
facilitation, such as DLF lesions or dermorphin-saporin conjugate
given into the RVM, also abolished dynorphin upregulation and
enhanced release of CGRP (111, 118, 119). Recent studies revealed
that increased concentrations of spinal dynorphin can stimulate
neurons through increased calcium influx, unexpectedly mediated
through the bradykinin receptors (120). Blockade of spinal brady-
kinin receptors inhibited behavioral signs of neuropathic pain, vis-
ceral pain, and diminished central sensitization (121–123). Collec-
tively, these studies suggest that descending facilitation represents
an important mechanism that likely contributes to maintenance
of central sensitization after peripheral nerve injury (78, 82).
Diffuse noxious inhibitory controls modulation of pain
The concept of diffuse noxious inhibitory control (DNIC) was for-
mulated from observations made with recordings of spinal dorsal
horn units in anesthetized rats in response to peripheral stimuli
applied to various parts of the body or electrical stimulation of
peripheral nerves (124, 125). It was found that peripheral noxious
stimuli suppressed the neuronal responses of convergent dorsal
horn units to either electrical stimulation of C-fibers or applica-
tion of noxious heat (124, 125). This inhibitory effect could be
evoked from noxious stimuli applied to various parts of the body
and thus was diffuse in nature (124, 125). Importantly, DNIC was
not demonstrated in dorsal horn units that responded solely to
noxious, proprioceptive, or innocuous inputs, indicating a require-
ment for convergent neurons receiving both noxious and innocu-
ous stimuli (125). In addition, DNIC was abolished by spinal cord
section and was diminished by systemic naloxone administration
(124–126). Visceral pain induced by i.p. injection of phenylben-
zoquinone inhibited vocalization induced by electrical stimuli
applied to the tail, and this inhibition was also dose-dependently
reversed by systemic naloxone (127). Observations that DNIC was
diminished by electrolytic lesion (128) or lidocaine microinjection
(129) of the nucleus raphe magnus suggested that there is a contri-
bution from this site to DNIC. However, other studies established
that lesions of the RVM or the PAG did not block DNIC (130) and
that DNIC was integrated at the level of the dorsal reticular nucle-
us (130). The dorsal reticular nucleus (DRt) receives nociceptive
inputs from spinal projections and communicates with the PAG
and RVM as well as the thalamus and amygdala and sends pain
modulatory projections to the spinal cord (131–133). Moreover,
the DRt sends and receives projections from cortical sites as well,
and a single DRt neuron can project to different CNS sites, thus
potentially modulating pain through several mechanisms (134).
The DRt, along with the PAG and the RVM, form parts of a spinal-
supraspinal-spinal feedback loop that modulates pain (134, 135).
Loss of DNIC and chronic pain
These observations suggest that many chronic pain syndromes
may be due in part to a loss of DNIC (136). Loss of DNIC could
manifest as enhanced through either the loss of endogenous inhibi-
tory control or an enhancement of pain facilitation (136). In one
recent study, patients with irritable bowel syndrome (IBS) or tem-
poromandibular disorder (TMD) or healthy volunteers received an
experimental pain stimulus in the form of increasing heat applied
by a probe placed on the palm and a conditioning pain stimulus in
the form of a foot-bath of noxious-cold water (137). The control
group demonstrated decreased sensitivity to the noxious thermal
stimulus when the foot was immersed in cold water, indicating
active DNIC, whereas not only was DNIC absent in the patients
with IBS or TMJ, but they showed enhanced sensitivity to the noci-
ceptive stimulus (137). The authors concluded from these data that
chronic pain could be caused in part by a deficient pain inhibitory
system (137). Deficits in DNIC have been demonstrated in patients
with a number of chronic pain syndromes, including, for example,
osteoarthritis of the knee (138), chronic pancreatitis (139), rheuma-
toid arthritis (140), and long-term trapezius myalgia (141).
Additionally, evidence is growing that a loss of DNIC suggests
that deficits in endogenous pain modulation may underlie chron-
ic tension-type headache (CTT) as well. In one study with CTT
patients and unafflicted volunteers, a training stimulus of noxious
thermal heat was applied to the thigh and an electrocutaneous
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3784 The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010
noxious stimulus was applied to either the forearm or the temple
(142). The control group demonstrated decreased pain perception
with the conditioning stimulus, whereas the CTT patients did not,
indicating a deficit of DNIC (142). Similarly, a more recent study
using pain from an occlusion cuff and temporal summation from
repeated pulses from a pressure algometer demonstrated deficien-
cy in DNIC in CTT patients (143). In a recent study performed
with rats, it was shown that persistent morphine exposure resulted
in increased sensitivity to sensory thresholds and loss of DNIC in
trigeminal neurons sensitive to dural stimulation (144). Here, it
was hypothesized that loss of DNIC may contribute to develop-
ment of medication-overuse headache (144). The DNIC paradigm
has been used as a clinical tool to predict who might be at risk for
enhanced postsurgical pain (145, 146).
Descending modulation and pain-relieving drugs
The existence of a descending pain modulatory system provides
many targets for the development of analgesic drugs or adjuncts
that enhance the effects of existing analgesics (Figure 2). Opi-
oids act throughout the neuraxis and can relieve pain through
activities at cortical and subcortical sites, at which affective and
somatosensory aspects of the pain experience can be modified, as
well as by activating descending pain inhibitory circuits. Activa-
tion of descending noradrenergic projections from the locus coe-
ruleus and other noradrenergic sites, described above, produces
antinociception. Accordingly, α2-adrenergic receptor agonists
have been shown to produce antinociception as well as to poten-
tiate the antinociceptive effect of opioids (94, 147). Moreover,
by increasing spinal noradrenergic activity, tricyclic antidepres-
sants and other selective noradrenergic reuptake inhibitors, such
as duloxetine, enhance the analgesic effect of opioids and show
clinical efficacy against neuropathic pain (148). It was recently
also shown that the clinical efficacy of gabapentin may be due to
its activation of descending noradrenergic systems and release of
norepinephrine in the spinal cord (149). The COX inhibitors exert
an analgesic effect by inhibition of PGE2 synthesis, thus reducing
peripheral and central sensitization. Recent studies also indicate
that inhibition of COX in the PAG promotes an opioid-mediated
descending pain inhibition (150).
Summary
The advent of neuroimaging studies and technological advances
allowing increased spatial and temporal resolution has contrib-
uted greatly to our changing perceptions of how pain is integrated
and modulated in the central nervous system. From early animal
studies that described a linear system of pain modulation from
the PAG through the RVM and descending to the spinal cord, we
now envision a complex pain matrix that includes important corti-
cal regions and elements of the limbic system as well as midbrain
and medullary sites. These structures that likely participate in pain
modulation reflect interacting brain regions that participate in
pain processing as well as autonomic regulation and sensory and
emotional management. The concept of top-down pain modula-
tion system accounts for or contributes to pain relief, as seen with
Figure 2
Schematic representation of bulbospinal pain inhibition and potential
targets of analgesic activity. (A) Descending pain inhibition from the
PAG can be initiated by electrical stimulation or direct microinjection
of opioids. Recent evidence also indicates a role for COX inhibitors in
the PAG as well. Opioids and cannabinoids inhibit pain by enhancing
the baseline firing rate of off-cells and eliminating the off-cell pause in
response to nociceptive stimuli. Inhibition of on-cell activity may abolish
enhanced pain states. The on-cells and off-cells might correlate with
pain facilitatory (+) and inhibitory (–) neurons in the RVM, respectively.
At the level of the spinal cord, opioids can inhibit transmitter release
from primary afferent terminals as well as activity of pain transmission
neurons. Norepinephrine (NE) release from spinopetal noradrenergic
fibers from medullary sites also inhibits pain transmission. Tricyclic
antidepressants (TCAs) and other norepinephrine reuptake inhibitors
enhance the antinociceptive effect of opioids by increasing the avail-
ability of spinal norepinephrine (box). Areas labeled “i–iii” in the small
diagram correspond with labeled details of the larger diagram. α2A,
α2-adrenergic receptor; DRG, dorsal root ganglion; SNRI, serotonin/
norepinephrine reuptake inhibitor; SP, substance P. (B) Mice deficient
in dopamine β-hydroxylase that do not produce norepinephrine show
a diminished antinociceptive effect of morphine compared with control
animals, suggesting that the presence of norepinephrine, presum-
ably released in the spinal cord, is required for the full expression of
morphine antinociception. The dashed line represents the 50% effect,
and the corresponding dose is the ED50 (that is the dose producing a
50% effect). % MPE, percentage maximal possible effect. ***P < 0.001
compared with the control group. Error bars represent SEM. Copyright
National Academy of Sciences, USA (151).
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The Journal of Clinical Investigation http://www.jci.org Volume 120 Number 11 November 2010 3785
the placebo effect, stress, DNIC, and the actions of pain-relieving
drugs, such as opioids, NSAIDs, reuptake blockers, and possibly
gabapentinoids. These modulatory pathways help to explain how
personal experience and emotional state as well as societal beliefs
may alter the experience of pain. Clinical evidence supports the
emerging view that dysfunctions of descending modulatory path-
ways, resulting in reduced inhibition/enhanced facilitation (e.g.,
loss of DNIC), can result in the enhanced pain observed in many
chronic pain conditions. While not yet clinically proven, enhanced
descending facilitation may also play an important role in main-
taining chronic pain. Increased knowledge of the components
of these clinically validated pain modulatory circuits may offer
approaches to develop improved pain therapy.
Acknowledgments
We thank Ian Meng, University of New England, for helpful com-
ments on the manuscript. This work was supported by NIH grants
DA012656, DA023513, and NS066958.
Address correspondence to: Frank Porreca, Department of Pharma-
cology, University of Arizona, Tucson, Arizona 85724, USA. Phone:
520.626.7421; Fax: 520.626.4182; E-mail: frankp@u.arizona.edu.
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