Mechanism of Neuropathic Pain

NIH Public Access
Author Manuscript
Neuron. Author manuscript; available in PMC 2007 March 6.
Published in final edited form as:
NIH-PA Author Manuscript
Neuron. 2006 October 5; 52(1): 77–92.
Mechanisms of Neuropathic Pain
James N. Campbell1,* and Richard A. Meyer1

1 Johns Hopkins University School of Medicine Baltimore, Maryland 21287
Abstract
Neuropathic pain refers to pain that originates from pathology of the nervous system. Diabetes,
infection (herpes zoster),nerve compression, nerve trauma, “channelopathies,” and autoimmune
disease are examples of diseases that maycause neuropathic pain. The development ofbothanimal
models and newer pharmacological strategies has led to an explosion of interest in the underlying
mechanisms. Neuropathic pain reflects both peripheral and central sensitization mechanisms.
Abnormal signals arise not only from injured axons but also from the intact nociceptors that share
the innervation territory of the injured nerve. This review focuses on how both human studies and
animal models are helping to elucidate the mechanisms underlying these surprisingly common
disorders. The rapid gain in knowledge about abnormal signaling promises breakthroughs in the
treatment of these often debilitating disorders.
Chronic pain has been estimated to affect one-sixth of the population. The phrase “neuropathic
pain” came into common use only in the last decade and increasingly has been appreciated as
a frequent source of chronic pain, perhaps trailing only osteoarthritis as a cause. Neuropathic
pain results from pathology in the nervous system. Consider the following clinical presentation:
A 47-year-old woman presented for consultation for complaints of pain on the right chest wall.
The patient underwent a mastectomy on the right side as a treatment for cancer 5 years
previously. As the surgical pain faded, the patient noted increasing chest-wall pain that
extended well beyond the surgical borders. Clothing lightly touching the skin increased the
pain. Reconstructive surgery was deferred because of concerns about the ongoing pain. In
addition to the ongoing burning pain, the patient also complained of sudden “pain attacks” one
to several times a day. These attacks lasted seconds to minutes and were described as
debilitating. Examination revealed a well-healed surgical scar. Light stroking of the skin
provoked significant pain in an area from the clavicle down to the T8 dermatome. Despite the
pain to light tactile stimuli, the patient also had areas of decreased sensibility as demonstrated
by the inability to detect a fine probe applied to the skin.
The above case represents a classical presentation of a patient with neuropathic pain. The
notable features that point to neuropathic processes are as follows:
• Widespread pain not otherwise explainable
• Evidence of sensory deficit
• Burning pain
• Pain to light stroking of the skin
• Attacks of pain without seeming provocation
The liability for pain appears to vary from person to person, from nerve to nerve, between
males and females, and even with age. What appears to be the same lesion may induce no pain
*Correspondence: [email protected].
Campbell and Meyer Page 2
in one person but severe pain in another. In addition to ongoing pain (i.e., stimulus-independent
pain), patients may have heightened pain to stimuli applied to their skin. This enhanced
stimulus-dependent pain is called hyperalgesia. In some patients, lightly stoking the skin may
evoke pain. This pain to light touch is often called allodynia (Treede et al., 1992).
In this review, we will focus on the mechanisms of neuropathic pain. Lesions of the CNS (e.g.,
spinal cord) and peripheral nerves may lead to pain, but the majority of experimental studies
have focused on consequences of lesions of peripheral nerves, and therefore, we will focus on
this area in this review.
Anatomical Considerations
Neuropathic pain is distinguished from other pain conditions where the pain generator begins
with disease of nonneural tissues. These nonneuropathic pain entities are said to be nociceptive
and include conditions such as osteoarthitis and inflammatory pain. By definition, neuropathic
pain originates from a lesion of the nervous system. Innumerable diseases may be the culprits.
Examples include autoimmune disease (e.g., multiple sclerosis), metabolic diseases (e.g.,
diabetic neuropathy), infection (e.g., shingles and the sequel, postherpetic neuralgia), vascular
disease (stroke), trauma, and cancer. A rule without apparent exception is that the lesion leading
to pain must directly involve the nociceptive pathways (Boivie et al., 1989). Accordingly, for
example, lesions of the medial lemniscal system (e.g., dorsal columns) do not induce pain
(Cook and Browder, 1965).
Whereas evidence supports the hypothesis that pain-generating lesions of the nervous system
must involve the nociceptive pathways, the converse clearly does not hold up. Namely, not all
lesions of nociceptive pathways induce pain. A lesion of the peripheral nerve may induce pain,
but simply severing dorsal roots seems to have little chance of creating lasting pain (Li et al.,
2000). For example, dorsal roots are cut to treat spasticity and sometimes to remove tumors.
The authors know of no case of neuropathic pain arising from these types of lesions in man.
Here, we do not take up the issue of CNS lesions, but it is nevertheless worth noting that though
spinal cord lesions carry a substantial risk of inducing pain, some evidence suggests that the
lesion must include the gray matter. Vireck has found that simple cordotomy where only the
white matter is lesioned does not induce abnormal pain behavior in a primate model, whereas
lesions that include the gray matter may (Vierck and Light, 1999). Lesions of the brainstem
and thalamus carry a risk of causing pain if the nociceptive pathways are involved (Boivie,
2006). In nearly all of these cases, there is the paradoxical juxtaposition of ongoing pain and
a sensory deficit to noxious stimulation (even when hyperalgesia is present). Lesions confined
to the cortex appear not to be associated with abnormal pain (but it is also unclear whether
lesions confined to the cerebral cortex induce deficits of pain sensibility [Head and Holmes,
1911]).
Nervous System Diseases Associated with Pain

As noted above, a rich variety of diseases of the nervous system are associated with pain (Table
1) (Scadding and Koltzenburg, 2006). In the introduction, a case of traumatic painful
neuropathy was presented (Campbell, 2001). The offending lesion may involve a simple
axotomy (cutting of the nerve) or merely nerve entrapment. Ongoing pain may be the only
manifestation, but in many cases, hyperalgesia with pain to light-stroking stimuli (allodynia)
may be manifest. In some cases, there is striking cooling hyperalgesia, where mild lowering
of skin temperature exacerbates the pain. Weir Mitchell described a striking variant of
neuropathic pain that he termed causalgia (Lau and Chung, 2004). He noted this condition in
patients who had missile lesions of an extremity. Patients presented with striking edema,
profound autonomic features (abnormal sweating and either hot or cold skin), and devastating
pain. A similar presentation can occur without a clear nerve injury, and presently, this is referred

to as “complex regional pain syndrome (CRPS), type 1.” Where a clear nerve lesion is manifest,
the condition is referred to as CRPS, type 2 (Stanton-Hicks et al., 1995).
One of the classic examples of neuropathic pain is Tic douloureux. Without treatment, this is
a debilitating disorder that involves attacks of severe pain in the facial area (also referred to as
trigeminal neuralgia). Often there is little or no pain between attacks. The lightening-like
attacks are referred to one of the dermatomes (V1, V2, or V3). Light touching of the skin in a
so-called trigger zone suffices to evoke an attack. The disease appears to be associated with
mechanical distortion at the entry zone of the nerve root to the brainstem. Demyelination may
be seen at the compression site. Nerve compression from an aberrant blood vessel is one of the
more common causes (Elias and Burchiel, 2002).
Another classical neuropathic pain condition is painful diabetic neuropathy (Dyck et al.,
2000). Diabetes often causes a length-dependent neuropathy (meaning that the longest axons
in the peripheral nerve are most vulnerable). Patients report bilateral burning pain in the toes
and feet. Quantitative sensory testing reveals decreased pain sensibility (with or without
decreased touch sensibility).
Postherpetic neuralgia is a complication of shingles and is an example of how an infection can

lead to pain. Shingles results from an activation of the herpes zoster virus that takes up residence
in the dorsal root ganglion after a chickenpox infection. The shingles eruption consists of
blisters that follow the dermatome(s) of one or more spinal nerves. The blisters heal in time,
but the pain may continue. Allodynia is a particularly prominent feature of postherpetic
neuralgia. This allodynia may be present even with loss of C-fiber innervation of the epidermis.
The clinical manifestations vary with the type of disease (Table 1). These variations suggest
different mechanisms. These differences in mechanism may also be reflected in responses to
therapy. Tic douloureux responds nicely to treatment with the anticonvulsant carbamazepine.
Responses to carbamazepine for other conditions are typically disappointing. Painful diabetic
neuropathy leads to ongoing pain, but allodynia is distinctly unusual, and cooling may relieve
pain. In contrast, allodynia is prominent in traumatic neuropathy and cooling often causes
severe pain.
Animal Models of Neuropathic Pain

Whereas the distinction between nociceptive and neuropathic pain has utility, in the actual
clinical setting, the mechanisms are often intertwined (e.g., back pain with radiculopathy).
Fortunately, however, this need not be the case with regard to animal models. A great advance
in the study of neuropathic pain emanated from the discovery that placement of loose chromic
ligatures on the sciatic nerve in rat brought about behavior that appeared analogous to human
neuropathic pain conditions (Bennett and Xie, 1988). The rats engaged in protective behavior
and had lowered thresholds to heat, cooling, and mechanical stimuli.
Subsequent work indicated that an idiosyncratic immune-mediated response to the chromic

suture played a major role in the development of the model (Maves et al., 1993). The nerve
swelled, leading to nerve compression and axotomy. But can an axotomy by itself induce pain?
The answer is unequivocally yes. Chung and colleagues (Kim and Chung, 1992) devised a now
frequently used model in rat whereby one or more spinal nerves that innervates the foot is cut
(SNL model in Figure 1A). A substantial innervation of the foot remains, reflecting input from
the adjacent spinal nerves. This remaining innervation allows tests for hyperalgesia to be
undertaken. A simple axotomy provides a foundation by which to study mechanism in diseases
where axotomy is part of the disease process. Some of the common traumatic nerve injury
models are illustrated in Figure 1A. These injuries lead to hyperalgesia (Figures 1B and 1C).

Trauma has not been the only model used in studies of neuropathic pain. One of the leading
causes of pain in humans is diabetic neuropathy. Injection of streptozotocin leads to an animal
model of diabetes and is associated with the development of neuropathy, similar to what is
seen in humans. Hyperalgesia can be measured in rodent models, thus providing a means to
study treatments and mechanisms of pain in this neuropathy model (Ahlgren and Levine,
1993). One of the dose-limiting problems in chemotherapy is neuropathy, and these
neuropathies are often associated with pain. Animal models of paclitaxel and vincristine-
induced painful neuropathies have been developed (Flatters and Bennett, 2004).
Though hyperalgesia is relatively easy to demonstrate in animal models, the measurement of

ongoing pain is more problematic. This issue is important because ongoing pain without clear
hyperalgesia appears to be a common occurrence in humans (Basbaum et al., 2006). Substantial
denervation of a limb in rat often leads to autotomy behavior. Some have advocated that
autotomy is an indication of ongoing pain, the presumed rationale being that the animal desires
to eliminate the painful body part (Devor, 1991). An alternative explanation is that the animal
chews an anesthetic part for reasons unrelated to pain. Some have argued that spontaneous foot
lifting may provide a behavioral measure of spontaneous pain (Djouhri et al., 2006). Alternative
measures of ongoing pain involve the use of cellular markers of increased neuronal activity.
Increased expression of the immediate early gene protein, c-Fos, in the dorsal horn (and perhaps
other more rostral sites) is an example (Bullitt, 1990). Small-animal functional magnetic
resonance imaging (fMRI) and/or PET imaging may in the future offer alternative measures.
Animal models of neuropathic pain in some cases have been inconsistent with human models.
Allodynia in painful diabetic neuropathy in humans is infrequent yet appears to be robust in
rat models. NK1 antagonists appeared to have promise for treatments of pain based on animal
models yet to date have not proven useful in patients. Vierck (2006) argues that “reflex”
measures of pain in animal neuropathic models are intrinsically flawed and are neither sensitive
nor specific predictors of drug efficacy in man. For example, he points out that the paw-
withdrawal threshold method tests motor neuron response rather than simply providing a
measure of pain. Moreover, he indicates that rostral signaling pathways may be ignored when
one merely measures the paw-withdrawal threshold. His solution is to utilize operant models.
However, operant measures may be flawed as well in that they introduce other complexities
such as motivational factors that may be extraneous to the question of how much pain is felt.
Furthermore, the simple paw-withdrawal technique has in fact demonstrated some consistency
with human pain studies. In a recent pharmacological study that used a paw-withdrawal method
in rodents with the SNL model (LaBuda and Little, 2005), hyperalgesia was reversed with
gabapentin, amitriptyline, and fluoxetine, but not indomethacin, treatment. This correlates with
the observation that the first three drugs are useful in treatment of neuropathic pain in humans
but that nonsteroidal drugs are in general not useful.
A careful comparison of operant and reflex models in terms of their predictive capacity has
yet to be performed. For drugs with a predominantly supraspinal action, operant measures may
be more appropriate, whereas simple paw-withdrawal thresholds may be sufficient for drugs
that work at peripheral or dorsal horn targets. Though the particulars of how pain is assessed
remain an issue, a greater concern may relate to substantial inherent differences in the biology
of nociception in rodent and man. Regardless of this, new drugs for treatment of neuropathic
pain have been developed, and their utility in animal models played an influential role in
moving these treatments into clinical trials.
Secondary Hyperalgesia and Central Sensitization

A starting place in understanding neuropathic pain is to consider what happens with injury to
nonneural tissues. Skin injury produces ongoing pain and two types of hyperalgesia: primary

and secondary (Meyer et al., 2006). Primary hyperalgesia occurs at the site of tissue injury and
is mediated in part by sensitization of primary afferent nociceptors. This is reflected by
increased responses to heat stimuli, for example. Secondary hyperalgesia occurs in the
uninjured tissue surrounding the site of injury and is thought to be due to sensitization in the
central nervous system. Secondary hyperalgesia is characterized by hyperalgesia to
mechanical, but not heat, stimuli. This mechanical hyperalgesia is comparable to the
hyperalgesia seen in patients with neuropathic pain. Two types of mechanical hyperalgesia are
observed: pain to light-stroking stimuli (i.e., allodynia) and enhanced pain to punctate stimuli.
Two psychophysical studies in human volunteers provide strong evidence that secondary
hyperalgesia is due to sensitization in the central nervous system. In both studies, intradermal
injection of capsaicin, the algesic substance in hot peppers, was used to produce a large zone
of secondary hyperalgesia. In the first study, the nerve supplying the area to be injected was
anesthetized with a local anesthetic (LaMotte et al., 1991). Injection of capsaicin still produced
a large flare, consistent with the concept that the flare reflects a peripherally mediated release
of vasoactive peptides subsequent to antidromic spread of action potentials in the nociceptive
terminals. In the opposite control arm, capsaicin injection at the same time produced intense
pain and a large zone of secondary hyperalgesia. When the anesthesia wore off, no zone of
mechanical hyperalgesia was found in the test arm, but hyperalgesia persisted in the control
arm. This experiment provides evidence that the barrage of nociceptor activity associated with
the capsaicin injection leads to an altered central processing of input from mechanosensitive
afferents.
In the second study, a fine electrode was placed into the superficial peroneal nerve (Torebjörk
et al., 1992). Electrical intraneural microstimulation produced a non-painful tactile percept that
was referred to a small zone on the top of the foot. Capsaicin was injected adjacent to this area
so that the zone of secondary hyperalgesia overlapped the area of referred sensation.
Microstimulation after the injection produced a painful percept. Because this stimulation
bypasses any peripheral sensitization processes at the cutaneous receptor, this experiment also
provides evidence for altered central processing of mechanoreceptor input. Additional studies
have shown that the tactile pain arises from central sensitization to the inputs of Aβ fibers,
whereas the punctate hyperalgesia is due to a central sensitization to the inputs of capsaicin-
insensitive Aδ nociceptors (Magerl et al., 2001).
The tactile fibers have known convergence onto dorsal horn cells that in addition receive inputs
from nociceptive primary afferents. The inputs from the nociceptors in the injury zone are
presumed to sensitize these so-called wide-dynamic range neurons and thereby enhance the
synaptic efficacy of the tactile fibers. Nociceptive-specific neurons (dorsal horn neurons in
lamina I) may be sensitized in similar fashion.
Central sensitization to the inputs of tactile afferents in patients has been demonstrated in
patients with neuropathic pain. A blood pressure cuff inflated in the proximal extremity leads
to an orderly loss of sensation beginning first with loss of tactile function. When this was done
in patients, the loss of tactile function coincided with loss of allodynia (Campbell et al.,
1988). It was also noted that the detection of pain with tactile stimuli was fast and indicated
that primary afferents transmitting the stimulus were likely in the A-β range.
Where Do the Abnormal Signals in Neuropathic Pain Originate?

As shown in Figure 2, multiple sites along the neural axis are altered after nerve injury.
Abnormalities occur in the injured and uninjured afferents supplying the affected region.
Central sensitization, similar to that discussed above following tissue injury, is observed. In
addition, changes in descending control systems have been reported. Finally, an immune
response, both peripherally and centrally, is observed.

A Role for Primary Afferents

The importance of primary afferent inputs in neuropathic pain is strongly suggested by several
pharmacological studies. For example, systemic administration of AM1241, a selective CB2

cannabinoid receptor agonist, results in reversal of signs of mechanical and thermal
hyperalgesia following an SNL lesion (Ibrahim et al., 2003). Because CB2 is not expressed in
the central nervous system, the effects are likely due to a peripheral mechanism.
Systemic administration of artemin dose-dependently reversed the behavioral signs of

neuropathic pain in rats with an SNL injury (Gardell et al., 2003). Artemin is a member of the
glial-derived neurotrophic factor (GDNF) family that signals through a common tyrosine
kinase receptor (RET) and GFRα3. GFRα3 is an accessory protein that is predominantly
expressed in small-diameter, unmyelinated neurons (Orozco et al., 2001). The artemin-induced
changes in neuropathic pain behavior are therefore most likely due to its action on nociceptive
primary afferents.
Antisense oligodeoxynucleotides (ODNs) directed against Nav 1.8 reversed signs of

mechanical hyperalgesia (Porreca et al., 1999). Nav 1.8 is a tetrodotoxin-resistant sodium
channel that is primarily expressed in small-diameter primary afferent neurons. This treatment
was effective even when applied 6–14 days after nerve injury, demonstrating that ongoing
peripheral neuronal input is critically involved in the maintenance of neuropathic pain.
The Injured Afferent Hypothesis

The above evidence makes a clear case for the role of primary afferents, and one might assume
that the culprit is the injured afferent itself. Indeed, much evidence favors this hypothesis. When
nerve is injured a neuroma forms. The spontaneous activity and ectopic sensitivity to
mechanical, thermal, and chemical stimuli that originate from the traumatic neuroma have been
well documented (Blumberg and Jänig, 1984; Devor, 2006a). Clinical evidence has suggested
that local-anesthetic blockade of an injured nerve in patients relieves pain, though no study,
surprisingly, has really addressed this issue in a well-designed blinded fashion (Arner et al.,
1990; Burchiel et al., 1993; Gracely et al., 1992; Koltzenburg et al., 1994). Additional support
for the role of injured afferents comes from experiments in the rat L5 SNL model in which
anesthetics (Sukhotinsky et al., 2004) or tetrodotoxin (TTX) (Lyu et al., 2000) directed at the
L5 ganglia reversed the neuropathic behavior.
Regardless of the reasonableness of the so-called injured afferent hypothesis, several lines of
evidence suggest that there is more to the story.
Surprisingly, several authors report that the L5 SNL model in rat leads to spontaneous activity
in A fiber, but not C fiber, afferents as recorded in the L5 dorsal root (Boucher et al., 2000;
Liu et al., 2000). This spontaneous activity in myelinated fibers appears to be produced mainly
in afferents that (preinjury) serve muscle and joint, but not skin (Michaelis et al., 2000; Proske
et al., 1995). These findings produce a dilemma because activity in C fibers is thought to be
necessary to evoke the central sensitization mechanisms that account for the hyperalgesia (Ji
and Woolf, 2001). One possible explanation is that A fiber-spontaneous activity can initiate
central sensitization after nerve injury, if the afferent undergoes a phenotypic switch. A de
novo expression of neuropeptides normally only expressed in nociceptive afferents could
occur. For example, substance P immunoreactivity increases in large- and medium-size DRG
neurons after axotomy (Noguchi et al., 1994). However, studies investigating substance P
release from myelinated afferents following nerve injury are inconclusive (Allen et al., 1999;
Malcangio et al., 2000). Another explanation is that the spontaneous activity occurs in “A-β”
nociceptors, the existence of which has been documented in rodent and primate (Djouhri and
Lawson, 2004; Treede et al., 1998).

Other behavioral data suggest that signals originating from the injured spinal nerve are not
essential for hyperalgesia to occur. An L5 dorsal rhizotomy immediately before or after an L5
spinal nerve ligation did not prevent or reverse neuropathic behavior (Eschenfelder et al.,
2000; Li et al., 2000). The counter to this observation is that dorsal rhizotomy by itself may
produce signs of mechanical hyperalgesia (Colburn et al., 1999; Eschenfelder et al., 2000).
More importantly, neuropathic pain behavior is observed after an L5 ganglionectomy, where
the injured afferents are removed altogether (Sheth et al., 2002). The prevailing message seems
to be that hyperalgesia can develop in the absence of neural activity from the injured nerve.
The Intact Nociceptor Hypothesis

According to this hypothesis, the intact nociceptors that survive injury and that innervate the
region affected by the transected nerve fibers sensitize and have spontaneous activity. These
changes in the intact nociceptors may induce ongoing pain and may account for certain aspects
of hyperalgesia.
Following peripheral nerve lesions in primate and rodent models, spontaneous activity
developed in uninjured, unmyelinated nociceptive afferents that shared the same innervation
terrritory of the transected fibers (Ali et al., 1999; Djouhri et al., 2006; Wu et al., 2001).
Although the average discharge frequency was low (seven action potentials/5 min), the
incidence of spontaneously active fibers was high (50%). Low rates of spontaneous activity
may therefore assume importance if this phenomenon is occurring in large numbers of C fibers,
in particular given the high convergence of C fiber input in the CNS. Consistent with this
hypothesis is the observation that low-frequency electrical stimulation in C fibers can lead to
hyperalgesia in humans (Klede et al., 2003) and behavioral signs of hyperalgesia in rats (Wu
et al., 2002). The development of spontaneous activity has also been observed in uninjured,
myelinated afferents in the L4 dorsal root (Boucher et al., 2000), and this activity originated
within the dorsal root ganglion.
Sensitization has also been reported in the intact nociceptors. Following peripheral or spinal
nerve lesion in rat or rabbit, uninjured afferents develop adrenergic sensitivity (Sato and Perl,
1991) and an increased sensitivity to tumor necrosis factor-α (TNFα) (Schäfers et al., 2003).
One study has suggested that sensitization to mechanical and heat stimuli occurs in the
uninjured, unmyelinated afferents as well (Shim et al., 2005). Increased responsiveness to heat
stimuli could be due to the observed increases in expression of mRNA and protein for the
transient receptor potential receptor V1 (TRPV1) in the DRG of uninjured afferents (Fukuoka
et al., 2000; Hudson et al., 2001). In addition, the incidence of cold-responsive neurons in the
L4 DRG is increased after an L5 SNL (Djouhri et al., 2004), and there is an increase in
expression of the putative cold-sensitive channel TRPA1 (Katsura et al., 2006). These
observations may account for the occurrence of cooling hyperalgesia seen in patients after
nerve trauma.
One compelling line of evidence in favor of the intact nociceptor hypothesis stems from
experiments where local treatments are applied to the partly denervated skin. Local treatments
can only affect the intact fibers. In patients, local treatment with capsaicin may significantly
relieve ongoing pain. This is of interest because the effects of capsaicin are specific to
nociceptors. Experiments with animal models point to similar conclusions. Mibefradil, a T-
type calcium-channel blocker, reversed mechanical and thermal hyperalgesia (Dogrul et al.,
2003), and local application of a glutamate receptor antagonist reversed signs of thermal
hyperalgesia (Dogrul et al., 2000). In both studies, contralateral injections were without effects.
Intraplantar injection of morphine on the ipsilateral, but not contralateral, side significantly
reversed mechanical allodynia (Pertovaara and Wei, 2001).

The intact L4 dorsal root ganglion has been studied extensively to determine changes in
phenotype after injury to the adjacent L5 spinal nerve (L5 SNL). In addition to increased
expression of TRPV1 and TRPA1, mRNA for calcitonin gene-related peptide (CGRP) is
upregulated (Fukuoka et al., 1998). Furthermore, the number of uninjured DRG neurons
expressing brain-derived neurotrophic factor (BDNF) is increased (Fukuoka et al., 2001). In
the SNI model, there is an upregulation of P2X3 mRNA in uninjured neurons (Tsuzuki et al.,
2001).
Sympathetically Maintained Pain and the Intact Nociceptor Hypothesis

CRPS is a striking disorder manifest by severe pain typically in an extremity. Patients typically
have edema, hyperalgesia, and may even have a motor disability that is difficult to explain
from a purely electrophysiological perspective. In certain of these patients, selective anesthetic
blockade of the sympathetic nervous system leads to dramatic relief of pain (sympathetically
maintained pain, or SMP). Blockade of α -adrenergic receptor function with intravenous
infusion of the antagonist phentolamine also leads to pain relief (Raja et al., 1991). In patients
with SMP, in whom a sympathetic ganglion block was done to relieve pain and block release
of norepinephrine, injection of physiological concentrations of norepinephrine evoked
substantial pain (Figure 3A).
In a primate model of neuropathic pain, an L6 SNL leads to hyperalgesia just as it does in

rodent models (Carlton et al., 1994). About one-half of the afferents to the top of the foot are
lost, and the other half reach the foot from the adjoining and putatively normal spinal nerves
(Ali et al., 1999). More than 60% of the intact nociceptors had spontaneous activity (normally
infrequently seen), and more than 50% had sensitivity to the select α -adrenergic agonist
phenylephrine (Figure 3B). These studies indicate that the mechanisms of SMP relate to an
adrenergic sensitization of nociceptors (Figure 3C). Moreover, this chemical sensitization
occurs in the intact nociceptors that survive a proximal nerve injury. Thus, SMP is a specific
example of the importance of the intact nociceptors in the pathogenesis of a particular
neuropathic pain disorder.
The Role of Growth Factors

Trophic factors in the target tissue have an ongoing influence on sensory and motor fibers.
Nerve injury induces changes in growth-factor expression (Griffin, 2006). The change in
expression occurs in the tissue deprived of innervation (e.g., the skin), the Schwann cells
affected by Wallerian degeneration (denervated Schwann cells), the DRG, and the dorsal horn.
Of note, in the SNL model, the L5 root is lesioned, but the L4 root shares the innervation
territory, the same Schwann cells, and has convergent input to dorsal horn cells served by the
L5 afferents. Nerve injury leads to increased levels of NGF in the skin supplied by L4. The
binding of this NGF to the Trk-A receptors on the L4 fibers leads to transport of NGF back to
the L4 DRG. Evidence suggests that this increased level of NGF in the L4 DRG affects factors
such as BDNF. Indeed, the changes in gene expression in the intact L4 DRG and the lesioned
L5 DRG are quite different.
Griffin has introduced the terms “undertrophed” and “overtrophed” to describe a putative
mechanism by which growth factors may dually affect both the injured and uninjured afferents
(Griffin, 2006). The injured axons by losing connectivity with the peripheral tissues lose trophic
influences. The increased expression of trophic factors in the denervated tissues on the other
hand “overtroph” the remaining (intact) fibers. NGF might be one of the villains in the case of
overtrophing, whereas GDNF might be the missing growth factor, absence of which generates
the pain-signaling mechanisms in the injured L5 spinal nerve (Boucher and McMahon,
2001).

Transduction, Channel Function, and Ectopic Discharge

Primary afferents transduce different forms of energy into generator potentials. If of sufficient
magnitude, these generator potentials lead to action potentials. The action potentials propagate
along the axon to the CNS. Pathological pain may result from disorders involved in any of
these steps.
There are two ways nociceptors may be sensitized. One is for the transduction channel to
sensitize (i.e., a bigger generator potential to a given natural stimulus). The other mechanism
regards a decrease in threshold of the sodium channels responsible for spike initiation. It is
logical therefore to ask whether primary afferent sensitization may account for features of
neuropathic pain. NGF regulates TRPV1 expression, and thus, over-trophing mechanisms
could link growth factors to transduction-channel function (Cortright and Szallasi, 2004). A
role for TRPV4, a channel that may be involved in transduction of mechanical stimuli, was
suggested in a neuropathic pain model produced by administration of taxol (Alessandri-Haber
et al., 2004). Abnormal transduction, at least in part, likely underlies the pathophysiology of
the “intact nociceptor.” Sensitization of the “intact” nociceptor in the SNL model may be
responsible for the hyperalgesia (Ringkamp and Meyer, 2006). Another mechanism relates to
the acquisition of transduction capacity for stimuli that ordinarily do not activate nociceptors.
This has been clearly demonstrated in the case of SMP, where intact nociceptors acquire
sensitivity to norepinephrine. Cooling hyperalgesia is prominent in neuropathic pain.
Abnormal expression of transduction channels such as TRPA1, or TRPM8 in nociceptors,
could account for this phenomenon.
Transduction can be displaced to a point of nerve injury as well. This misplaced transduction
could account for the so-called “Tinel sign,” a useful clinical finding, wherein patients
experience paresthesias (tingling sensation) or dysthesthesia (an unpleasant or frankly painful
sensation) when the area over the nerve injury is tapped. The Tinel sign may be present at a
point of entrapment where continuity of the axon has not necessarily been interrupted. The
presumed mechanism is that a disturbance of fast axonal transport (which serves as delivery
mechanism for newly synthesized transduction proteins) leads to ectopic expression of the
transduction proteins. Axotomy leads to neuroma formation, where budding regenerative nerve
sprouts devoid of growth guidance from denervated Schwann cells form an entangled mass.
Many neuromas are “painful,” but for unclear reasons (genetic factors, location?) many are
not. Areas of nerve injury may be tethered to adjacent moving structures (e.g., tendons), such
that otherwise normal movements evoke an increase in pain presumably by activating
nociceptive afferents through activation of mechanoreceptive transduction channels.
Nociceptor sensitization could also relate to changes in voltage-gated sodium channels,

particularly in the region of spike initiation (Devor, 2006b). For example, if the threshold for
sodium-channel activation decreases, the response to a given generator potential will be

enhanced.
One reason for interest in sodium-channel function centers on clinical evidence that drugs that
affect sodium-channel function may be very effective in relieving neuropathic pain. For
example, the anticonvulsant carbamazepine, which works by stabilizing sodium channels in
an inactive state, is considered the treatment of choice for trigeminal neuralgia. The effects are
consistent enough that clinicians are trained to question the diagnosis if the patient does not
have at least some response to the drug. As a class, each of the anticonvulsants that work
through a sodium-channel mechanism (lamotrigine, phenytoin, in addition to carbamazepine)
have some level of efficacy in neuropathic pain, though side effects often preclude usefulness.
Another class of drugs that is effective in neuropathic pain is the local anesthetics (Tremont-
Lukats et al., 2006). At doses that have no effect on normal sensibility, local anesthetics may
favorably affect neuropathic pain.

There are multiple types of voltage-gated sodium channels that are expressed in the dorsal root
ganglion and may have a role in neuropathic pain. The channels that have received greatest
interest are Nav 1.3, 1.7, 1.8, and 1.9. These channels are found in small DRG cells and therefore
are likely involved in action potential generation and conduction in nociceptors. Channels
Nav 1.3 and 1.7 are TTX sensitive, whereas Nav 1.8 and 1.9 are TTX insensitive. Some animal
data suggest that TTX given systemically may relieve hyperalgesia without adversely affecting
normal functions (Marcil et al., 2006). Of the channels tested, only the TTX-sensitive channel
Nav 1.3 is upregulated in the DRG of the injured axons (Black et al., 1999). This channel has
kinetic properties that could favor repetitive spiking.
Whereas prior efforts have concentrated on the α -subunit expression, other complexities affect
sodium-channel function. Expression of the β subunits could be part of this complexity. β2
subunits regulate channel gating, assembly, and cell-surface expression of TTX-sensitive
channels. Expression of these subunits is increased in injured sensory afferents (Pertin et al.,
2005), and in β2 null mice, mechanical hyperalgesia is reduced in a spared nerve injury model.
β2 null mice display marked reduction in TTX-sensitive sodium current in small DRG neurons
(Lopez-Santiago et al., 2006).
That channel function may strongly affect nociception has been further emphasized by the
discovery of the genetic underpinnings of a striking neuropathic pain disorder known as
erythromelalgia. Here, patients present with profound heat hyperalgesia and ongoing burning
pain typically affecting the feet. The feet may also be intensely red, indicating profound
vasodilation. Point mutations in the TTX-sensitive channel Nav1.7 account for the disorder
(Figure 4). These mutations lead to a hypo-excitability in sympathetic neurons (accounting for
the increased perfusion in the feet) and a hyperexcitability in small-sensory neurons
(accounting for the pain and hyperalgesia) (Rush et al., 2006). Release of vasoactive peptides
in the skin from the tonically active nociceptors may also contribute to the vasodilatation.
The Role of Central Sensitization

Central sensitization refers to the augmented response of central signaling neurons. Though
thalamic and cortical levels may be involved, most attention has focused on the dorsal horn
and in this review we will concentrate on this area.
When it occurs as a result of inflammation, central sensitization is strongly dependent on

ongoing input from nociceptors. Thus, if nociceptive input is blocked in the injury zone,
secondary hyperalgesia abates promptly (LaMotte et al., 1991). This same dependence on
peripheral input probably also applies to central sensitization associated with neuropathic pain,
but this issue requires further clarification. This distinction is of great importance clinically. If
mechanisms of pain are completely centralized, it might be argued that attention to peripheral
mechanisms is unlikely to be therapeutically beneficial.
Central sensitization involves homosynaptic and heterosynaptic mechanisms (Magerl et al.,

1998; Woolf et al., 1988). Homosynaptic sensitization means that the conditioning stimulus
and the test stimulus involve the same input. In dorsal horn nociceptive neurons, this is evident
in a phenomenon referred to as “windup,” where continual low-frequency stimulation of C
fiber afferents leads to an increasing response in the dorsal horn cell. Windup lasts tens of
seconds and represents a short-term form of sensitization.
Herterosynaptic sensitization means that the conditioning stimulus and the test stimulus involve
different sets of afferents. Heterosynaptic sensitization accounts for allodynia. Here,
nociceptive inputs alter synaptic efficacy such that A-β mechanoreceptors acquire the capacity
to evoke responses. Electrophysiological evidence for heterosynaptic sensitization has been

shown in primate studies of dorsal horn cells where the response to light stroking of the skin
was enhanced after capsaicin injection (Simone et al., 1991).
Ample evidence indicates that heterosynaptic and homosynaptic sensitization occur in

neuropathic pain conditions (Campbell et al., 1988; Ji et al., 2003). Figure 5 provides a model
for how this may occur in the L5 SNL model of neuropathic pain. Injured myelinated fibers
from the L5 root develop spontaneous activity. Some of this activity could be in A-β
mechanoreceptors (that have acquired the capacity to release substance P) or in A-δ
nociceptors. The input of these fibers onto cells in the L5 segment could lead to homosynaptic
sensitization and enhanced ongoing activity. The enhanced activity in L5 spinal thalamic tract
cells could play a role in ongoing pain sensation. The injured L5 afferents could also project
to the adjacent L4 segment where they could produce heterosynaptic sensitization to input from
the L4 segment. This could account for the hyperalgesia to mechanical and heat stimuli that is
signaled by activity in the intact L4 afferents.
Uninjured nociceptors in L4 root can develop spontaneous activity after an L5 SNL. This
spontaneous activity can lead to homosynaptic sensitization such that stimulus-evoked activity
in these nociceptors results in an augmented response of the dorsal horn cells. The spontaneous
activity in uninjured L4 nociceptors could also produce heterosynaptic sensitization such that
the response of L4 spinal thalamic cells to L4 mechanoreceptor input is enhanced. A brush
stimulus applied to the foot activates the A-β fibers in the L4 root and acquires the capacity to
drive activity in the L4 dorsal horn cell, consistent with heterosynaptic sensitization.
Homosynaptic and heterosynaptic sensitization involve many mechanisms, but fundamentally

these mechanisms come down to two processes: (1) increased release of excitatory
neurotransmitter (e.g., glutamate, substance P) and/or (2) enhanced synaptic efficacy. These
changes in turn may relate to several cellular mechanisms (Basbaum, 1999). These mechanisms
may be considered in five categories: (1) presynaptic changes, (2) postsynaptic changes, (3)
interneuron changes, (4) changes in descending modulation, and (5) immune/microglial
mechanisms (discussed in the following section). Evidence suggests a role for each of these
mechanisms in neuropathic pain. Long-term potentiation (LTP), a phenomenon that has
received intensive study in the hippocampus, appears to apply to the dorsal horn to some degree.
However, given the abnormal ongoing input of primary afferents documented after nerve
injury, the acute central-sensitizing effects of primary afferents may have an ongoing role.
Thus, both short-term sensitization and LTP mechanisms likely apply. A role for long-term
depression (LTD) in inhibitory cells is also considered below.
Presynaptic Mechanisms
Release of glutamate is inhibited presynaptically by several metabotropic G protein-coupled
receptors, including μ-opioid receptors, GABA-b, and adenosine receptors. Downregulation

of μ-opioid receptors has been documented both pre- and postsynaptically after nerve injury
(Kohno et al., 2005) and could lead to an enhanced release of glutamate.
Neurotransmitter release is triggered by voltage-gated calcium channel activity on the central

terminals of primary afferents. Nerve injury leads to an upregulation of the α -2-δ subunit of
these channels in the DRG and spinal cord (Li et al., 2004). This could be associated with
increased calcium entry and augmented release of glutamate. The anticonvulsant drugs
gabapentin and pregabalin are effective in neuropathic pain presumably because they bind to
and block this subunit (Bian et al., 2006; Freynhagen et al., 2005). Although these drugs reverse
hyperalgesia in neuropathic models, there is no apparent effect on normal pain sensibility
(Suzuki et al., 2005). This argues for a special role of the α -2 subunit in neuropathic pain.

There is also evidence to suggest that under conditions of nerve injury, A-β fibers undergo a
phenotypic switch, such that they begin to express substance P (Noguchi et al., 1994). As a
consequence, stimulation of these fibers leads to substance P release, providing an additional
potential mechanism for sensitization of dorsal horn neurons.
Postsynaptic Mechanisms
There is excellent documentation of the role of postsynaptic mechanisms in central
sensitization. Slow depolarization induced by substance P and other peptides leads to an
opening of the NMDA glutamate-gated channel, which in turn leads to calcium entry
(Dougherty et al., 1993; Duggan, 1995; Yoshimura and Yonehara, 2006). Calcium may gain
entry through AMPA receptors that do not contain the GluR2 subunit, as well, and this
mechanism may play a role in dorsal horn LTP (Gu et al., 1996). A conditional knockdown of
one NMDA subunit, NR1, abolished hyperalgesia to formalin but had no effect on normal pain
sensibility (South et al., 2003). Evidence exists for a multitude of intracellular events linked
to postsynaptic sensitization that result from calcium entry. Protein kinases A and C and other
transcriptional factors likely play important roles in these events (Kawasaki et al., 2004).
Another possible mechanism of postsynaptic sensitization involves an increased trafficking of

AMPA receptors to the cell surface. The expression of AMPA receptors is increased in the
superficial dorsal horn after an SNL lesion (Harris et al., 1996). In addition, upregulation of
the mRNAs for both AMPA and NMDA receptors has been demonstrated in diabetes
(Tomiyama et al., 2005).
We have suggested that allodynia stems from sensitization to the inputs of tactile afferents in
the dorsal horn. However, certain evidence suggests that the “Aβ sensitization” phenomenon
may actually arise from alternative pathways. A lesion of the ipsilateral dorsal column
abolished mechanical hyperalgesia but, interestingly, not heat hyperalgesia (Ossipov et al.,
2002; Sun et al., 2001). These data suggest that dorsal horn trafficking may account for heat
hyperalgesia but that other centers, such as the thalamus, may actually account for the allodynia.
Role of Disinhibition Mechanisms

Inhibitory neurons play an important role in governing the sensitivity of dorsal horn neurons
(Gu et al., 1996). Decreased expression of inhibitory receptors (on primary afferent terminals
and postsynaptic neurons) has been noted following nerve injury, and sensitization could result
from this disinhibition mechanism (Kohno et al., 2005). Several other mechanisms involving
inhibitory interneurons have been suggested. We have discussed LTP. The reciprocal
phenomenon is LTD. Salter has suggested that LTD may be evoked by activation of NMDA
receptors present on GABAergic cells due to differential expression of the subunits in the
NMDA receptor (Salter, 2006). LTD in inhibitory cells may lead to central sensitization
(Randic et al., 1993). To what extent this mechanism applies to the dorsal horn is unclear.
Nerve injury also induces a downregulation of the potassium-chloride transporter KCC2. This
trans-synaptic effect on superficial dorsal horn cells (presumed projection neurons of the
spinothalamic tract), leads to a less-negative equilibrium potential for chloride, such that
opening the chloride channel with GABA induces depolarization sufficient to induce
excitation. Consistent with this finding, knockdown of the expression of KCC2 leads to
hyperalgesia (Coull et al., 2003).
Further evidence indicates that nerve injury induces a selective apoptosis of inhibitory
GABAergic inter-neurons (Moore et al., 2002). Apoptosis of inhibitory GABAergic neurons
argues for a hard-wire change in circuitry (Scholz et al., 2005). This is a critical therapeutic
issue. If central sensitization evolves such that nociceptive signaling becomes independent of

inputs from primary afferents, then treating the peripheral nerve may no longer be
therapeutically useful. Moreover, the relative importance of peripheral and central mechanisms
may well depend on the underlying disease. Some diseases may involve primary afferents as
well as the CNS. An example is postherpetic neuralgia where damage may extend from the
primary afferents to the dorsal horn.
Descending Modulatory Mechanisms

Descending modulatory pathways also appear to influence dorsal horn sensitization
mechanisms in neuropathic pain. Cortical, thalamic, and periaqueductal inputs converge on
the rostroventromedial medulla (RVM). This center gives rise to both inhibitory and excitatory
inputs to the dorsal horn via an ipsilateral pathway in the dorsolateral funiculus (DLF). Many
of the cells in the RVM express μ-opioid receptors. Selective ablation of these cells either
before or after establishment of the SNL model can eliminate hyperalgesia (Porreca et al.,
2001). Lidocaine microinjection (Burgess et al., 2002) and hemisection experiments (Bian et
al., 1998) have yielded similar results.
Supraspinal Mechanisms
Recent fMRI studies reveal changes in the processing of cutaneous stimuli at supraspinal
centers in conditions of hyperalgesia and allodynia. Experimental studies of secondary
hyperalgesia allow the comparison of fMRI images before and after the development of
hyperalgesia. In these studies, mechanical stimulation of the skin produced enhanced pain in
the zone of secondary hyperalgesia and led to enhanced activation in areas of the brain
associated with pain signaling (Baron et al., 1999; Maihofner et al., 2004). Whether these
changes in supraspinal processing are passive or whether they reflect additional plasticity
mechanisms is difficult to know. Functional imaging studies in patients with neuropathic pain
reveal that light stroking that produces pain recruits a complex cortical network, including
nociceptive, motor, and cognitive areas (Maihofner et al., 2006; Schweinhardt et al., 2006).
Functional imaging may lead to new insights into the mechanisms of neuropathic pain as well
as to objective measures of altered sensations (Borsook et al., 2004).
The Immune System and Neuropathic Pain

Clearly the immune system is critical to the pain associated with inflammatory pain. The
immune system appears to play a critical role in neuropathic pain as well (Marchand et al.,
2005). Nude rats that lack mature T cells had diminished hyperalgesia (Moalem et al., 2004).
Passive transfer of type 1, but not type 2, T cells led to similar levels of hyperalgesia as those
seen in rats with intact T cell function. In addition, cytokines, II-1, II-6, and TNFα all have
demonstrated roles in neuropathic pain (Manning, 2006). Several variables are worth noting
in approaching the question of immune mechanisms.

• One must distinguish the immune mechanisms associated with a particular disease
from the immune mechanisms that are particular to the issue of neuropathic pain.
• Immune mechanisms need to be considered separately in terms of what happens in
the peripheral nervous system versus those that are important in the central nervous
system.
• Finally, immune mechanisms may play a role in initiating neuropathic pain,
maintaining neuropathic pain acutely, and/or play a role in chronic neuropathic pain.
Peripheral Immune Mechanisms

Nociceptors have a rich variety of immune receptors, and evidence exists for roles of the
interleukins (IL-1β and IL-6), TNFα, bradykinin, prostanoids, and others (Opree and Kress,

2000). In the CCI model of neuropathic pain, a “neuritis” develops, likely reflecting the
inflammatory response to the suture material (Kleinschnitz et al., 2004). In this model, immune
mechanisms might be a particular issue simply because of the foreign suture material. A more
interesting question is what happens with simple surgical axotomy (e.g., the SNL model).
Nerve damage evokes a cascade of immune responses. Nerve damage leads to macrophage
infiltration, T cell activation, and increased expression of proinflammatory cytokines. With
axotomy, Schwann cells are in a sense denervated. These denervated Schwann cells (as well
as cells in the partially denervated target tissue) may communicate with intact fibers that pass
within the same nerve. This provides a mechanism by which to explain changes in the intact
nociceptor (see above). Schwann cell denervation recruits macrophages via secretion of
leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 (MCP-1) (Sugiura
et al., 2000). MCP-1 serves as a ligand for CCR2 (Tofaris et al., 2002). CCR2 knockout mice
do not develop mechanical hyperalgesia after a partial nerve ligation injury (Abbadie et al.,
2003). Cytokine IL-1β leads to increased expression of nerve growth factor (NGF), and NGF
may sensitize nociceptors (Kanaan et al., 1998). Knockout of the IL-1 receptor type I and
genetically mediated overexpression of an IL-1 receptor antagonist decreased hyperalgesia.
That the effect was peripheral was supported by the observation that spontaneous activity
recorded from the dorsal root fibers was reduced (Wolf et al., 2006).
TNFα has received much attention as a culprit in neuropathic pain. Endoneurial administration
induces hyperalgesia (Wagner and Myers, 1996). Preemptive treatment with the TNF-
sequestering drug etanercept decreases hyperalgesia but has no effect once hyperalgesia is
established (Sommer et al., 2001). TNFα can initiate activity in nociceptors (Sorkin et al.,
1997). Inhibition of TNFα blocks phosphorylation of the MAP kinase p38 in DRG and
hyperalgesia but again only when given preemptively (Schäfers et al., 2003). Another cytokine
that has received attention is IL-6. A role in the CCI model has been suggested (Okamoto et
al., 2001), but other peripheral actions are unclear at present.
Central Immune Mechanisms

Somewhat surprising is the mounting evidence that central immune mechanisms play a role in
neuropathic pain (Figure 6) (Watkins and Maier, 2005). As with peripheral mechanisms, much
evidence supports the view that initiation, but not maintenance, of neuropathic pain behaviors
is associated with immune mechanisms (Xu et al., 2006). Microglia serve as the macrophages
of the CNS. Nerve injury distal to the dorsal root ganglia leads to microglial activation.
However, activation after dorsal rhizotomy is much less, in keeping with the observation that
dorsal rhizotomy leads to less-impressive hyperalgesia compared to spinal nerve lesions
involving the identical root (Willis et al., 2006). Interthecal delivery of the antibiotic
minocycline, an inhibitor of microglial activation, attenuates neuropathic pain (Raghavendra
et al., 2003).
The mechanisms are far from clear. Nociceptor activity leads to rapid activation of the MAP
kinase ERK in microglia and initially not in other central cells (Tsuda et al., 2005). Inhibition
of this activation attenuates pain behavior. The mechanisms for this activation might be multi-
factorial. Evidence exists for a role of the ATP receptors P2X4 and/or P2X7, both of which
are expressed on microglia. The chemokine fractalkine may also be involved, as blockade of
its receptor, CX3CR1, attenuates hyperalgesia in neuropathic pain models (Milligan et al.,
2005). The activated microglia produce the toxic cytokines IL-1, IL-6, and TNFα as well as
nitric oxide, excitatory amino acids, ATP, and prostaglandins (Inoue, 2006).
The toll-like receptor-4 (TLR4) is a molecule involved in the innate immune response and is
mainly expressed on microglia. Spinal mRNA for TLR4 is increased after L5 SNL. A knockout
or point mutation in TLR4, as well as downregulation through intrathecal delivery of anti-sense

ODN, has a significant effect on neuropathic pain behavior, but only when given in the early
stages (Tanga et al., 2005).
Conclusion
We began this review by presenting a patient with chest-wall pain following a mastectomy.
The simultaneous finding of decreased sensation and ongoing pain was suggested to be a
paradox. Animal models, as well as studies in humans, however, have taken us a long way
toward understanding this case of neuropathic pain. Ongoing pain likely represents
spontaneous discharge in afferents. The injured afferents are an obvious source of abnormal
input.
Sodium-channel dysfunction likely plays an important role in leading to ectopic generation of

action potentials. The patient had episodes of abrupt “pain attacks.” These attacks may
correspond to bursts of spontaneous activity in the injured afferents related to sodium-channel
dysfunction. Somewhat surprisingly, however, the intact afferents that share the innervation
territory of the injured afferents also discharge spontaneously. Studies of their cell bodies in
the DRG reveal striking phenotype changes. Trophic factors released from the partly
denervated skin working through their receptors on the peripheral terminals may account for
these abnormalities. The abnormalities seen in these “intact” nociceptors likely account for the
fact that patients such as this may respond to therapies applied at the level of the skin. Central
changes also play a role in neuropathic pain. Many of the mechanisms probably are the same
as those observed with inflammatory pain. The patient had pain and hyperalgesia well outside
the region of nerve injury. This is precisely the case in inflammatory pain, where secondary
hyperalgesia extends well beyond the injury site. The patient had substantial pain when the
skin was lightly stroked (allodynia). Multiple lines of evidence indicate that this allodynia is
due to central sensitization, such that tactile afferents acquire synaptic efficacy, which enables
them to trigger activity in central pain signaling neurons. Prevailing work has focused on the
dorsal horn as the site for this sensitization, but more rostral pathways may be involved as well.
Though not easily understood as yet, peripheral nerve injury induces some striking transynaptic
effects. One is apoptosis that appears to preferentially affect GABA inhibitory cells. Several
lines of evidence indicate that immune mechanisms are involved both peripherally and
centrally. Activation of microglial cells occurs in the dorsal horn, and this activation may play
a vital role in initiating central sensitization. The role of this activation in ongoing neuropathic
pain is less clear. The sensation of pain begins with a simple thesis: nociceptors encode
information about noxious stimuli and propagate these messages to the CNS and pain is felt.
In the case of neuropathic pain, however, we see that a rich biology is at play. Studies are
quickly uncovering the mechanisms, and no longer can we consider the presence of this
problem quite so mysterious.
Acknowledgements
We greatly appreciated the suggestions from Drs. Jasenka Borzan, Michael Caterina, and Matthias Ringkamp on earlier
drafts of this manuscript and the technical assistance of Cheryl Carmona. This research was supported by the National
Institutes of Health (NS-014447 and NS-041269) and the Blaustein Pain Treatment Center.
References
Abbadie C, Lindia JA, Cumiskey AM, Peterson LB, Mudgett JS, Bayne EK, DeMartino JA, MacIntyre
DE, Forrest MJ. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2.
Proc Natl Acad Sci USA 2003;100:7947–7952. [PubMed: 12808141]
Ahlgren SC, Levine JD. Mechanical hyperalgesia in streptozotocin-diabetic rats. Neuroscience
1993;52:1049–1055. [PubMed: 8450973]

Alessandri-Haber N, Dina OA, Yeh JJ, Parada CA, Reichling DB, Levine JD. Transient receptor potential
vanilloid 4 is essential in chemotherapy-induced neuropathic pain in the rat. J Neurosci 2004;24:4444–
4452. [PubMed: 15128858]
Ali Z, Ringkamp M, Hartke TV, Chien HF, Flavahan NA, Campbell JN, Meyer RA. Uninjured C-fiber
nociceptors develop spontaneous activity and alpha adrenergic sensitivity following L6 spinal nerve
ligation in the monkey. J Neurophysiol 1999;81:455–466. [PubMed: 10036297]
Ali Z, Raja SN, Wesselmann U, Fuchs PN, Meyer RA, Campbell JN. Intradermal injection of
norepinephrine evokes pain in patients with sympathetically maintained pain. Pain 2000;88:161–168.
[PubMed: 11050371]
Allen BJ, Li J, Menning PM, Rogers SD, Ghilardi J, Mantyh PW, Simone DA. Primary afferent fibers
that contribute to increased substance P receptor internalization in the spinal cord after injury. J
Neurophysiol 1999;81:1379–1390. [PubMed: 10085363]
Arner S, Lindblom U, Meyerson BA, Molander C. Prolonged relief of neuralgia after regional anesthetic
blocks. A call for further experimental and systematic clinical studies. Pain 1990;43:287–297.
[PubMed: 1705693]
Baron R, Baron Y, Disbrow E, Roberts TP. Brain processing of capsaicin-induced secondary
hyperalgesia: a functional MRI study. Neurology 1999;53:548–557. [PubMed: 10449119]
Basbaum AI. Distinct neurochemical features of acute and persistent pain. Proc Natl Acad Sci USA
1999;96:7739–7743. [PubMed: 10393891]
Basbaum, AI.; Bushnell, MC.; Campbell, JN.; Chaplan, SR.; Mantyh, PW.; Porreca, F.; Price, DD.;
Urban, L.; Vierck, CJ.; Zubieta, JK. Measurrement and new technologies: rapporteur report. In
Emerging Strategies for the Treatment of Neuropathic. In: Campbell, JN.; Basbaum, AI.; Dray, A.;
Dubner, R.; Dworkin, RH.; Sang, CN., editors. Pain. Seattle, WA: IASP Press; 2006. p. 361-381.
Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like
those seen in man. Pain 1988;33:87–107. [PubMed: 2837713]
Bian D, Ossipov MH, Zhong C, Malan TP Jr, Porreca F. Tactile allodynia, but not thermal hyperalgesia,
of the hindlimbs is blocked by spinal tansection in rats with nerve injury. Neurosci Lett 1998;241:79–
82. [PubMed: 9507925]
Bian F, Li Z, Offord J, Davis MD, McCormick J, Taylor CP, Walker LC. Calcium channel alpha2-delta
type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and
spinal cord: an ex vivo autoradiographic study in alpha2-delta type 1 genetically modified mice.
Brain Res 2006;1075:68–80. [PubMed: 16460711]
Black JA, Cummins TR, Plumpton C, Chen YH, Hormuzdiar W, Clare JJ, Waxman SG. Upregulation
of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. J
Blumberg H, Jänig W. Discharge pattern of afferent fibers from a neuroma. Pain 1984;20:335–353.
[PubMed: 6097859]
Boivie, J. Central pain. In: McMahon, SB.; Koltzenburg, M., editors. Wall and Melzack’s Textbook of
Pain. London: Elsevier; 2006. p. 1057-1074.
Boivie J, Leijon G, Johansson I. Central post-stroke pain–a study of the mechanisms through analyses
of the sensory abnormalities. Pain 1989;37:173–185. [PubMed: 2748190]

Borsook D, Burstein R, Becerra L. Functional imaging of the human trigeminal system: opportunities
for new insights into pain processing in health and disease. J Neurobiol 2004;61:107–125. [PubMed:
15362156]
Boucher TJ, McMahon SB. Neurotrophic factors and neuropathic pain. Curr Opin Pharmacol 2001;1:66–
72. [PubMed: 11712538]
Boucher TJ, Okuse K, Bennett DL, Munson JB, Wood JN, McMahon SB. Potent analgesic effects of
GDNF in neuropathic pain states. Science 2000;290:124–127. [PubMed: 11021795]
Bullitt E. Expression of C-fos-like protein as a marker for neuronal activity following nixious stimulation
in the rat. J Comp Neurol 1990;296:517–530. [PubMed: 2113539]
Burchiel KJ, Johans TJ, Ochoa J. The surgical treatment of painful traumatic neuromas. J Neurosurg
1993;78:714–719. [PubMed: 8468601]

Burgess SE, Gardell LR, Ossipov MH, Malan TP Jr, Vanderah TW, Lai J, Porreca F. Time-dependent
descending facilitation from the rostral ventromedial medulla maintains, but does not initiate,
neuropathic pain. J Neurosci 2002;22:5129–5136. [PubMed: 12077208]
Campbell JN. Nerve lesions and the generation of pain. Muscle Nerve 2001;24:1261–1273. [PubMed:
11562904]
Campbell JN, Raja SN, Meyer RA, Mackinnon SE. Myelinated afferents signal the hyperalgesia
associated with nerve injury. Pain 1988;32:89–94. [PubMed: 3340426]
Carlton SM, Lekan HA, Kim SH, Chung JM. Behavioral manifestations of an experimental model for
peripheral neuropathy produced by spinal nerve ligation in the primate. Pain 1994;56:155–166.
[PubMed: 8008406]
Colburn RW, Rickman AJ, DeLeo JA. The effect of site and type of nerve injury on spinal glial activation
and neuropathic pain behavior. Exp Neurol 1999;157:289–304. [PubMed: 10364441]
Cook AW, Browder EJ. Function of Posterior columns in man. Arch Neurol 1965;12:72–79. [PubMed:
14224862]
Cortright DN, Szallasi A. Biochemical pharmacology of the vanilloid receptor TRPV1. An update Eur J
Biochem 2004;271:1814–1819.
Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, De Koninck P, De Koninck Y. Trans-
synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature
2003;424:938–942. [PubMed: 12931188]
Cummins TR, Dib-Hajj SD, Waxman SG. Electro-physiological properties of mutant Nav1.7 sodium
channels in a painful inherited neuropathy. J Neurosci 2004;24:8232–8236. [PubMed: 15385606]
Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain.
Pain 2000;87:149–158. [PubMed: 10924808]
Devor M. Sensory basis of autotomy in rats. Pain 1991;45:109–110. [PubMed: 1843450]
Devor, M. Response of nerves to injury in relation to neuropathic pain. In: McMahon, SB.; Koltzenburg,
M., editors. Wall and Melzack’s Textbook of Pain. London: Elsevier; 2006a. p. 905-927.
Devor M. Sodium channels and mechanisms of neuropathic pain. J Pain 2006b;7:S3–S12. [PubMed:
16426998]
Djouhri L, Lawson SN. Abeta-fiber nociceptive primary afferent neurons: a review of incidence and
properties in relation to other afferent A-fiber neurons in mammals. Brain Res Brain Res Rev
2004;46:131–145. [PubMed: 15464202]
Djouhri L, Wrigley D, Thut PD, Gold MS. Spinal nerve injury increases the percentage of cold-responsive
DRG neurons. Neuroreport 2004;15:457–460. [PubMed: 15094503]
Djouhri L, Koutsikou S, Fang X, McMullan S, Lawson SN. Spontaneous pain, both neuropathic and
inflammatory, is related to frequency of spontaneous firing in intact C-fiber nociceptors. J Neurosci
2006;26:1281–1292. [PubMed: 16436616]
Dogrul A, Ossipov MH, Lai J, Malan TP Jr, Porreca F. Peripheral and spinal antihyperalgesic activity of
SIB-1757, a metabotropic glutamate receptor (mGLUR(5)) antagonist, in experimental neuropathic
pain in rats. Neurosci Lett 2000;292:115–118. [PubMed: 10998562]
Dogrul A, Gardell LR, Ossipov MH, Tulunay FC, Lai J, Porreca F. Reversal of experimental neuropathic
pain by T-type calcium channel blockers. Pain 2003;105:159–168. [PubMed: 14499432]
Dougherty PM, Palecek J, Zorn S, Willis WD. Combined application of excitaory amino acids and
substance P produces long-lasting changes in responses of primate spinothalamic tract neurons. Brain
Res Brain Res Rev 1993;18:227–246. [PubMed: 7687919]
Duggan AW. Release of neuropeptides in the spinal cord. Prog Brain Res 1995;104:197–223. [PubMed:
8552769]
Dyck PJ, Dyck PJ, Larson TS, O’Brien PC, Velosa JA. Patterns of quantitative sensation testing of
hypoesthesia and hyperalgesia are predictive of diabetic polyneuropathy: a study of three cohorts.
Nerve growth factor study group. Diabetes Care 2000;23:510–517. [PubMed: 10857944]
Elias WJ, Burchiel KJ. Microvascular decompression. Clin J Pain 2002;18:35–41. [PubMed: 11803301]
Eschenfelder S, Häbler HJ, Jänig W. Dorsal root section elicits signs of neuropathic pain rather than
reversing them in rats with L5 spinal nerve injury. Pain 2000;87:213–219. [PubMed: 10924814]

Flatters SJ, Bennett GJ. Ethosuximide reverses paclitaxel- and vincristine-induced painful peripheral
neuropathy. Pain 2004;109:150–161. [PubMed: 15082137]
Freynhagen R, Strojek K, Griesing T, Whalen E, Balkenohl M. Efficacy of pregabalin in neuropathic
pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of

flexible- and fixed-dose regimens. Pain 2005;115:254–263. [PubMed: 15911152]
Fukuoka T, Tokunaga A, Kondo E, Miki K, Tachibana T, Noguchi K. Change in mRNAs for
neuropeptides and the GABA(A) receptor in dorsal root ganglion neurons in a rat experimental
neuropathic pain model. Pain 1998;78:13–26. [PubMed: 9822208]
Fukuoka, T.; Tokunaga, A.; Kondo, E.; Noguchi, K. The role of neighboring intact dorsal root ganglion
neurons in a rat neuropathic pain model. In: Devor, M.; Rowbotham, M.; Wiesenfeld-Hallin, Z.,
editors. Progress in Pain Research and Management. Seattle, WA: ISAP Press; 2000. p. 137-146.
Fukuoka T, Kondo E, Dai Y, Hashimoto N, Noguchi K. Brain-derived neurotrophic factor increases in
the uninjured dorsal root ganglion neurons in selective spinal nerve ligation model. J Neurosci
2001;21:4891–4900. [PubMed: 11425916]
Gardell LR, Wang R, Ehrenfels C, Ossipov MH, Rossomando AJ, Miller S, Buckley C, Cai AK, Tse A,
Foley SF, et al. Multiple actions of systemic artemin in experimental neuropathy. Nat Med
2003;9:1383–1389. [PubMed: 14528299]
Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: altered central processing maintained
dynamically by peripheral input. Pain 1992;51:175–194. [PubMed: 1484715]
Griffin, JW. The roles of growth factors in painful length-dependent axonal neuropathies. In Emerging
Strategies for the Treatment of Neuropathic. In: Campbell, JN.; Basbaum, AI.; Dray, A.; Dubner, R.;
Dworkin, RH.; Sang, CN., editors. Pain. Seattle, WA: IASP Press; 2006. p. 271-290.
Gu JG, Albuquerque C, Lee CJ, MacDermott AB. Synaptic strengthening through activation of Ca2+-
permeable AMPA receptors. Nature 1996;381:793–796. [PubMed: 8657283]
Harris JA, Corsi M, Quartaroli M, Arban R, Bentivoglio M. Upregulation of spinal glutamate receptors
in chronic pain. Neuroscience 1996;74:7–12. [PubMed: 8843072]
Head H, Holmes GM. Sensory disturbances from cerebral lesions. Brain 1911;34:102–254.
Hudson LJ, Bevan S, Wotherspoon G, Gentry C, Fox A, Winter J. VR1 protein expression increases in
undamaged DRG neurons after partial nerve injury. Eur J Neurosci 2001;13:2105–2114. [PubMed:
11422451]
Ibrahim MM, Deng H, Zvonok A, Cockayne DA, Kwan J, Mata HP, Vanderah TW, Lai J, Porreca F,
Makriyannis A, Malan TP Jr. Activation of CB2 cannabinoid receptors by AM1241 inhibits
experimental neuropathic pain: pain inhibition by receptors not present in the CNS. Proc Natl Acad
Sci USA 2003;100:10529–10533. [PubMed: 12917492]
Inoue K. The function of microglia through purinergic receptors: Neuropathic pain and cytokine release.
Pharmacol Ther 2006;109:210–226. [PubMed: 16169595]
Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: implications for the
initiation and maintenance of pathological pain. Neurobiol Dis 2001;8:1–10. [PubMed: 11162235]
Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar
mechanisms? Trends Neurosci 2003;26:696–705. [PubMed: 14624855]

Kanaan SA, Poole S, Saade NE, Jabbur S, Safieh-Garabedian B. Interleukin-10 reduces the endotoxin-
induced hyperalgesia in mice. J Neuroimmunol 1998;86:142–150. [PubMed: 9663559]
Katsura H, Obata K, Mizushima T, Yamanaka H, Kobayashi K, Dai Y, Fukuoka T, Tokunaga A,
Sakagami M, Noguchi K. Antisense knock down of TRPA1, but not TRPM8, alleviates cold
hyperalgesia after spinal nerve ligation in rats. Exp Neurol 2006;200:112–123. [PubMed: 16546170]
Kawasaki Y, Kohno T, Zhuang ZY, Brenner GJ, Wang H, Van Der Meer C, Befort K, Woolf CJ, Ji RR.
Ionotropic and metabotropic receptors, protein kinase A, protein kinase C, and Src contribute to C-
fiber-induced ERK activation and cAMP response element-binding protein phosphorylation in dorsal
horn neurons, leading to central sensitization. J Neurosci 2004;24:8310–8321. [PubMed: 15385614]
Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal
nerve ligation in the rat. Pain 1992;50:355–363. [PubMed: 1333581]
Klede M, Handwerker HO, Schmelz M. Central origin of secondary mechanical hyperalgesia. J

Kleinschnitz C, Brinkhoff J, Zelenka M, Sommer C, Stoll G. The extent of cytokine induction in

peripheral nerve lesions depends on the mode of injury and NMDA receptor signaling. J
Neuroimmunol 2004;149:77–83. [PubMed: 15020067]
Kohno T, Ji RR, Ito N, Allchorne AJ, Befort K, Karchewski LA, Woolf CJ. Peripheral axonal injury
results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord. Pain
2005;117:77–87. [PubMed: 16098668]
Koltzenburg M, Torebjörk HE, Wahren LK. Nociceptor modulated central sensitization causes
mechanical hyperalgesia in acute chemogenic and chronic neuropathic pain. Brain 1994;117:579–
591. [PubMed: 8032867]
LaBuda CJ, Little PJ. Pharmacological evaluation of the selective spinal nerve ligation model of
neuropathic pain in the rat. J Neurosci Methods 2005;144:175–181. [PubMed: 15910975]
LaMotte RH, Shain CN, Simone DA, Tsai EFP. Neurogenic hyperalgesia: Psychophysical studies of
underlying mechanisms. J Neurophysiol 1991;66:190–211. [PubMed: 1919666]
Lau FH, Chung KC. Silas Weir Mitchell, MD: the physician who discovered causalgia. J Hand Surg
[Am] 2004;29:181–187.
Li CY, Song YH, Higuera ES, Luo ZD. Spinal dorsal horn calcium channel alpha2delta-1 subunit
upregulation contributes to peripheral nerve injury-induced tactile allodynia. J Neurosci
2004;24:8494–8499. [PubMed: 15456823]
Li Y, Dorsi MJ, Meyer RA, Belzberg AJ. Mechanical hyperalgesia after an L5 spinal nerve lesion in the
rat is not dependent on input from injured nerve fibers. Pain 2000;85:493–502. [PubMed: 10781924]
Liu CN, Wall PD, Ben Dor E, Michaelis M, Amir R, Devor M. Tactile allodynia in the absence of C-
fiber activation: altered firing properties of DRG neurons following spinal nerve injury. Pain
2000;85:503–521. [PubMed: 10781925]
Lopez-Santiago LF, Pertin M, Morisod X, Chen C, Hong S, Wiley J, Decosterd I, Isom LL. Sodium
channel beta2 subunits regulate tetrodotoxin-sensitive sodium channels in small dorsal root ganglion
neurons and modulate the response to pain. J Neurosci 2006;26:7984–7994. [PubMed: 16870743]
Lyu YS, Park SK, Chung K, Chung JM. Low dose of tetrodotoxin reduces neuropathic pain behaviors
in an animal model. Brain Res 2000;871:98–103. [PubMed: 10882788]
Magerl W, Wilk SH, Treede RD. Secondary hyperalgesia and perceptual wind-up following intradermal
injection of capsaicin in humans. Pain 1998;74:257–268. [PubMed: 9520240]
Magerl W, Fuchs PN, Meyer RA, Treede RD. Roles of capsaicin-insensitive nociceptors in cutaneous
pain and secondary hyperalgesia. Brain 2001;124:1754–1764. [PubMed: 11522578]
Maihofner C, Schmelz M, Forster C, Neundorfer B, Handwerker HO. Neural activation during
experimental allodynia: a functional magnetic resonance imaging study. Eur J Neurosci
2004;19:3211–3218. [PubMed: 15217377]
Maihofner C, Handwerker HO, Birklein F. Functional imaging of allodynia in complex regional pain
syndrome. Neurology 2006;66:711–717. [PubMed: 16534108]
Malcangio M, Ramer MS, Jones MG, McMahon SB. Abnormal substance P release from the spinal cord
following injury to primary sensory neurons. Eur J Neurosci 2000;12:397–399. [PubMed: 10651897]
Manning, D. The role of neuroimmune activation in chronic neuropathic pain and new targets for
therapeutic intervention. In Emerging Strategies for the Treatment of Neuropathic. In: Basbaum, AI.;
Campbell, JN.; Dray, A.; Dubner, R.; Dworkin, RH.; Sang, CN., editors. Pain. Seattle, WA: IASP
Press; 2006. p. 161-192.
Marchand F, Perretti M, McMahon SB. Role of the immune system in chronic pain. Nat Rev Neurosci
2005;6:521–532. [PubMed: 15995723]
Marcil J, Walczak JS, Guindon J, Ngoc AH, Lu S, Beaulieu P. Antinociceptive effects of tetrodotoxin
(TTX) in rodents. Br J Anaesth 2006;96:761–768. [PubMed: 16675510]
Maves TJ, Pechman PS, Gebhart GF, Meller ST. Possible chemical contribution from chromic gut sutures
produces disorders of pain sensation like those seen in man. Pain 1993;54:57–69. [PubMed: 8378104]
Meyer, RA.; Ringkamp, M.; Campbell, JN.; Raja, SN. Peripheral mechanisms of cutaneous nociception.
In: McMahon, SB.; Koltzenburg, M., editors. Wall and Melzack’s Textbook of Pain. London:
Elsevier; 2006. p. 3-34.

Michaelis M, Liu X, Jänig W. Axotomized and intact muscle afferents but not skin afferents develop
ongoing discharges of dorsal root ganglion origin after peripheral nerve lesion. J Neurosci
2000;20:2742–2748. [PubMed: 10729355]
Milligan E, Zapata V, Schoeniger D, Chacur M, Green P, Poole S, Martin D, Maier SF, Watkins LR. An
initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a
neuronally released chemokine. Eur J Neurosci 2005;22:2775–2782. [PubMed: 16324111]
Moalem G, Xu K, Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury
in rats. Neuroscience 2004;129:767–777. [PubMed: 15541898]
Moore KA, Kohno T, Karchewski LA, Scholz J, Baba H, Woolf CJ. Partial peripheral nerve injury
promotes a selective loss of GABAergic inhibition in the superficial dorsal horn of the spinal cord.
J Neurosci 2002;22:6724–6731. [PubMed: 12151551]
Noguchi K, Dubner R, De Leon M, Senba E, Ruda MA. Axotomy induces preprotachykinin gene
expression in a sub-population of dorsal root ganglion neurons. J Neurosci Res 1994;37:596–603.
[PubMed: 7518007]
Okamoto K, Martin DP, Schmelzer JD, Mitsui Y, Low PA. Pro- and anti-inflammatory cytokine gene
expression in rat sciatic nerve chronic constriction injury model of neuropathic pain. Exp Neurol
2001;169:386–391. [PubMed: 11358451]
Opree A, Kress M. Involvement of the proinflammatory cytokines tumor necrosis factor-alpha, IL-1 beta,
and IL-6 but not IL-8 in the development of heat hyperalgesia: effects on heat-evoked calcitonin
gene-related peptide release from rat skin. J Neurosci 2000;20:6289–6293. [PubMed: 10934280]
Orozco OE, Walus L, Sah DW, Pepinsky RB, Sanicola M. GFRalpha3 is expressed predominantly in
nociceptive sensory neurons. Eur J Neurosci 2001;13:2177–2182. [PubMed: 11422460]

Ossipov MH, Zhang ET, Carvajal C, Gardell L, Quirion R, Dumont Y, Lai J, Porreca F. Selective
mediation of nerve injury-induced tactile hypersensitivity by neuropeptide Y. J Neurosci
2002;22:9858–9867. [PubMed: 12427842]
Pertin M, Ji RR, Berta T, Powell AJ, Karchewski L, Tate SN, Isom LL, Woolf CJ, Gilliard N, Spahn DR,
Decosterd I. Upregulation of the voltage-gated sodium channel beta2 subunit in neuropathic pain
models: characterization of expression in injured and non-injured primary sensory neurons. J
Neurosci 2005;25:10970–10980. [PubMed: 16306410]
Pertovaara A, Wei H. Peripheral effects of morphine in neuropathic rats: role of sympathetic
postganglionic nerve fibers. Eur J Pharmacol 2001;429:139–145. [PubMed: 11698036]
Porreca F, Lai J, Bian D, Wegert S, Ossipov MH, Eglen RM, Kassotakis L, Novakovic S, Rabert DK,
Sangameswaran L, Hunter JC. A comparison of the potential role of the tetrodotoxin-insensitive
sodium channels, PN3/SNS and NaN/SNS2, in rat models of chronic pain. Proc Natl Acad Sci USA
1999;96:7640–7644. [PubMed: 10393873]
Porreca F, Burgess SE, Gardell LR, Vanderah TW, Malan TP Jr, Ossipov MH, Lappi DA, Lai J. Inhibition
of neuropathic pain by selective ablation of brainstem medullary cells expressing the muopioid
receptor. J Neurosci 2001;21:5281–5288. [PubMed: 11438603]
Proske U, Iggo A, Luff AR. Mechanical sensitivity of regenerating myelinated skin and muscle afferents
in the cat. Exp Brain Res 1995;104:89–98. [PubMed: 7542609]
Raghavendra V, Tanga F, Rutkowski MD, DeLeo JA. Anti-hyperalgesic and morphine-sparing actions
of propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia
and proinflammatory cytokines. Pain 2003;104:655–664. [PubMed: 12927638]
Raja SN, Treede RD, Davis KD, Campbell JN. Systemic alpha-adrenergic blockade with phentolamine:
a diagnostic test for sympathetically maintained pain. Anesthesiology 1991;74:691–698. [PubMed:
1848966]
Randic M, Jiang MC, Cerne R. Long-term potentiation and long-term depression of primary afferent
neurotransmission in the rat spinal cord. J Neurosci 1993;13:5228–5241. [PubMed: 8254370]
Ringkamp, M.; Meyer, RA. Does peripheral sensitization of primary afferents play a role in neuropathic
pain? In Emerging Strategies for the Treatment of Neuropathic. In: Campbell, JN.; Basbaum, AI.;
Dray, A.; Dubner, R.; Dworkin, RH.; Sang, CN., editors. Pain. Seattle, WA: IASP Press; 2006. p.
87-102.

Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation
produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci USA
2006;103:8245–8250. [PubMed: 16702558]
Salter, MW. Signaling pathways in pain neuroplasticity in the spinal dorsal horn. In: Campbell, JN.;
Basbaum, AI.; Dray, A.; Dubner, R.; Dworkin, RH.; Sang, CN., editors. Emerging Strategies for
the Treatment of Neuropathic Pain. Seattle, WA: IASP Press; 2006. p. 193-209.
Sato J, Perl ER. Adrenergic excitation of cutaneous pain receptors induced by peripheral nerve injury.
Science 1991;251:1608–1610. [PubMed: 2011742]
Scadding, JW.; Koltzenburg, M. Painful peripheral neuropathies. In: McMahon, SB.; Koltzenburg, M.,
editors. Wall and Melzack’s Textbook of Pain. London: Elsevier; 2006. p. 973-999.
Schäfers M, Lee DH, Brors D, Yaksh TL, Sorkin LS. Increased sensitivity of injured and adjacent
uninjured rat primary sensory neurons to exogenous tumor necrosis factor-alpha after spinal nerve
ligation. J Neurosci 2003;23:3028–3038. [PubMed: 12684490]
Scholz J, Broom DC, Youn DH, Mills CD, Kohno T, Suter MR, Moore KA, Decosterd I, Coggeshall RE,
Woolf CJ. Blocking caspase activity prevents transsynaptic neuronal apoptosis and the loss of
inhibition in lamina II of the dorsal horn after peripheral nerve injury. J Neurosci 2005;25:7317–
7323. [PubMed: 16093381]
Schweinhardt P, Glynn C, Brooks J, McQuay H, Jack T, Chessell I, Bountra C, Tracey I. An fMRI study
of cerebral processing of brush-evoked allodynia in neuropathic pain patients. Neuroimage
2006;32:256–265. [PubMed: 16679031]
Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats
by partial sciatic nerve injury. Pain 1990;43:205–218. [PubMed: 1982347]

Sheth RN, Dorsi MJ, Li Y, Murinson BB, Belzberg AJ, Griffin JW, Meyer RA. Mechanical hyperalgesia
after an L5 ventral rhizotomy or an L5 ganglionectomy in the rat. Pain 2002;96:63–72. [PubMed:
11932062]
Shim B, Kim DW, Kim BH, Nam TS, Leem JW, Chung JM. Mechanical and heat sensitization of
cutaneous nociceptors in rats with experimental peripheral neuropathy. Neuroscience
2005;132:193–201. [PubMed: 15780478]
Simone DA, Sorkin LS, Oh U, Chung JM, Owens C, LaMotte RH, Willis WD. Neurogenic hyperalgesia:
Central neural correlates in responses of spinothalamic tract neurons. J Neurophysiol 1991;66:228–
246. [PubMed: 1919669]
Sommer C, Lindenlaub T, Teuteberg P, Schafers M, Hartung T, Toyka KV. Anti-TNF-neutralizing
antibodies reduce pain-related behavior in two different mouse models of painful mononeuropathy.
Brain Res 2001;913:86–89. [PubMed: 11532251]
Sorkin LS, Xiao WH, Wagner R, Myers RR. Tumour necrosis factor-α induces ectopic activity in
nociceptive primary afferent fibres. Neuroscience 1997;81:255–262. [PubMed: 9300418]
South SM, Kohno T, Kaspar BK, Hegarty D, Vissel B, Drake CT, Ohata M, Jenab S, Sailer AW, Malkmus
S, et al. A conditional deletion of the NR1 subunit of the NMDA receptor in adult spinal cord dorsal
horn reduces NMDA currents and injury-induced pain. J Neurosci 2003;23:5031–5040. [PubMed:
12832526]
Stanton-Hicks M, Janig W, Hassenbusch S, Haddox JD, Boas R, Wilson P. Reflex sympathetic dystrophy:
changing concepts and taxonomy. Pain 1995;63:127–133. [PubMed: 8577483]
Sugiura S, Lahav R, Han J, Kou SY, Banner LR, de Pablo F, Patterson PH. Leukaemia inhibitory factor
is required for normal inflammatory responses to injury in the peripheral and central nervous
systems in vivo and is chemotactic for macrophages in vitro. Eur J Neurosci 2000;12:457–466.
[PubMed: 10712626]
Sukhotinsky I, Ben Dor E, Raber P, Devor M. Key role of the dorsal root ganglion in neuropathic tactile
hypersensibility. Eur J Pain 2004;8:135–143. [PubMed: 14987623]
Sun H, Ren K, Zhong CM, Ossipov MH, Malan TP, Lai J, Porreca F. Nerve injury-induced tactile
allodynia is mediated via ascending spinal dorsal column projections. Pain 2001;90:105–111.
[PubMed: 11166976]
Suzuki R, Rahman W, Rygh LJ, Webber M, Hunt SP, Dickenson AH. Spinal-supraspinal serotonergic
circuits regulating neuropathic pain and its treatment with gabapentin. Pain 2005;117:292–303.
[PubMed: 16150546]

Tanga FY, Nutile-McMenemy N, DeLeo JA. The CNS role of Toll-like receptor 4 in innate
neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 2005;102:5856–5861. [PubMed:
15809417]
Tofaris GK, Patterson PH, Jessen KR, Mirsky R. Denervated Schwann cells attract macrophages by
secretion of leukemia inhibitory factor (LIF) and monocyte chemoattractant protein-1 in a process
regulated by interleukin-6 and LIF. J Neurosci 2002;22:6696–6703. [PubMed: 12151548]
Tomiyama M, Furusawa K, Kamijo M, Kimura T, Matsunaga M, Baba M. Upregulation of mRNAs
coding for AMPA and NMDA receptor subunits and metabotropic glutamate receptors in the dorsal
horn of the spinal cord in a rat model of diabetes mellitus. Brain Res Mol Brain Res 2005;136:275–
281. [PubMed: 15893611]
Torebjörk HE, Lundberg LER, LaMotte RH. Central changes in processing of mechanoreceptive input
in capsaicin-induced secondary hyperalgesia in humans. J Physiol 1992;448:765–780. [PubMed:
1593489]
Treede RD, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous
hyperalgesia. Prog Neurobiol 1992;38:397–421. [PubMed: 1574584]
Treede RD, Meyer RA, Campbell JN. Myelinated mechanically insensitive afferents from monkey hairy
skin: heat-response properties. J Neurophysiol 1998;80:1082–1093. [PubMed: 9744923]
Tremont-Lukats IW, Hutson PR, Backonja MM. A randomized, double-masked, placebo-controlled pilot
trial of extended IV lidocaine infusion for relief of ongoing neuropathic pain. Clin J Pain
2006;22:266–271. [PubMed: 16514327]
Tsuda M, Inoue K, Salter MW. Neuropathic pain and spinal microglia: a big problem from molecules in
“small” glia. Trends Neurosci 2005;28:101–107. [PubMed: 15667933]

Tsuzuki K, Kondo E, Fukuoka T, Yi D, Tsujino H, Sakagami M, Noguchi K. Differential regulation of
P2X(3) mRNA expression by peripheral nerve injury in intact and injured neurons in the rat sensory
ganglia. Pain 2001;91:351–360. [PubMed: 11275393]
Vierck, CJ. Animal studies of pain: lessons for drug development. In Emerging Strategies for the
Treatment of Neuropathic. In: Campbell, JN.; Basbaum, AI.; Dray, A.; Dubner, R.; Dworkin, RH.;
Sang, CN., editors. Pain. Seattle, WA: IASP Press; 2006. p. 475-496.
Vierck CJ Jr, Light AR. Effects of combined hemotoxic and anterolateral spinal lesions on nociceptive
sensitivity. Pain 1999;83:447–457. [PubMed: 10568853]
Wagner R, Myers RR. Endoneurial injection of TNF-alpha produces neuropathic pain behaviors.
Neuroreport 1996;7:2897–2901. [PubMed: 9116205]
Watkins LR, Maier SF. Immune regulation of central nervous system functions: from sickness responses
to pathological pain. J Intern Med 2005;257:139–155. [PubMed: 15656873]
Waxman SG, Dib-Hajj S. Erythermalgia: molecular basis for an inherited pain syndrome. Trends Mol
Med 2005;11:555–562. [PubMed: 16278094]
Willis, WD., Jr; Hammond, DL.; Dubner, R.; Merzenich, M.; Eisenach, JC.; Salter, MW.; Iyengar, S.;
Shippenberg, T. Central nervous system targets: rapporteur report. In Emerging Strategies for the
Treatment of Neuropathic. In: Campbell, JN.; Basbaum, AI.; Dray, A.; Dubner, R.; Dworkin, RH.;
Sang, CN., editors. Pain. Seattle, WA: IASP Press; 2006. p. 105-122.
Wolf G, Gabay E, Tal M, Yirmiya R, Shavit Y. Genetic impairment of interleukin-1 signaling attenuates
neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in
mice. Pain 2006;120:315–324. [PubMed: 16426759]
Woolf CJ, Thompson SW, King AE. Prolonged primary afferent induced alterations in dorsal horn
neurones, an intra-cellular analysis in vivo and in vitro. J Physiol (Paris) 1988;83:255–266.
[PubMed: 3272296]
Wu G, Ringkamp M, Hartke TV, Murinson BB, Campbell JN, Griffin JW, Meyer RA. Early onset of
spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J
Neurosci 2001;21:RC140. [PubMed: 11306646]
Wu G, Ringkamp M, Murinson BB, Pogatzki EM, Hartke TV, Weerahandi HM, Campbell JN, Griffin
JW, Meyer RA. Degeneration of myelinated efferent fibers induces spontaneous activity in
uninjured C-fiber afferents. J Neurosci 2002;22:7746–7753. [PubMed: 12196598]

Xu JT, Xin WJ, Zang Y, Wu CY, Liu XG. The role of tumor necrosis factor-alpha in the neuropathic
pain induced by Lumbar 5 ventral root transection in rat. Pain 2006;123:306–321. [PubMed:
16675114]
Yen LD, Bennett GJ, Ribeir-oda-Silva A. Sympathetic sprouting and changes in nociceptive sensory
innervation in the glabrous skin of the rat hind paw following partial peripheral nerve injury. J Comp
Neurol 2006;495:679–690. [PubMed: 16506190]
Yoshimura M, Yonehara N. Alteration in sensitivity of ionotropic glutamate receptors and tachykinin
receptors in spinal cord contribute to development and maintenance of nerve injury-evoked
neuropathic pain. Neurosci Res 2006;56:21–28. [PubMed: 16901566]

Figure 1. Animal Models of Neuropathic Pain

(A) Four different nerve injury models are shown. In the spinal nerve ligation (SNL) model,
one or more spinal nerves going to the foot are ligated and cut (Kim and Chung, 1992). In the
partial sciatic ligation (PSL) model, a portion of the sciatic nerve is tightly ligated (Seltzer et
al., 1990). The chronic constriction injury (CCI) model involves placement of four loose
chromic-gut ligatures on the sciatic nerve. An immune response to the sutures leads to nerve
swelling and nerve constriction. In the spared nerve injury (SNI) model, the common peroneal
and tibial nerves are cut, sparing the sural nerve (Decosterd and Woolf, 2000). In each model,
only a portion of the afferents going to the foot are lesioned.
(B and C) Each of these nerve injury models leads to hyperalgesia, which is manifest by
enhanced responses to mechanical, heat, and/or cooling stimuli. (B) To test for mechanical
hyperalgesia, Von Frey monofilaments with different bending forces are applied to the plantar
surface of the foot. The threshold force for paw withdrawal decreases dramatically after the
nerve injury (adapted with permission [Li et al., 2000])
(C) To test for heat hyperalgesia, a radiant heat source is focused onto the plantar surface of
the foot, and the reaction time for paw withdrawal is measured. The difference in reaction time
between the ipsilateral and contralateral foot is calculated. After the SNL, the withdrawal of
the ipsilateral foot is faster than the contralateral foot (negative latency difference), indicating
the presence of heat hyperalgesia (adapted from Kim and Chung [1992] reprinted from Pain,
pp. 355–363, copyright 1992, with permission from the International Association for the Study
of Pain).
Data are presented as mean ± SEM.

Figure 2. A Spinal Nerve Injury Leads to Alterations at Many Sites along the Neural Axis for Pain
Eight different sites of pathophysiological changes are shown. (1) Spontaneous neural activity
and ectopic sensitivity to mechanical stimuli develops at the site of nerve injury. (2) The
expression of different molecules in the dorsal root ganglion of the injured nerve is up- or
downregulated, reflecting the loss of trophic support from the periphery. Spontaneous neural
activity develops in the dorsal root ganglia. (3) The distal part of the injured nerve undergoes
Wallerian degeneration, exposing the surviving nerve fibers from uninjured portions of the
nerve to a milieu of cytokines and growth factors. (4) Partial denervation of the peripheral
tissues leads to an excess of trophic factors from the partly denervated tissue that can lead to
sensitization of primary afferent nociceptors. (5) The expression of different molecules in the
dorsal root ganglion of the uninjured nerve is up- or downregulated, reflecting the enhanced
trophic support from the periphery. (6) Sensitization of the postsynaptic dorsal horn cell
develops, leading to an augmentation of the response to cutaneous stimuli. (7) Activated
microglial cells contribute to the development of this dorsal horn sensitization. (8) Changes in
descending modulation of dorsal horn neurons also may contribute to the enhanced
responsiveness of dorsal horn neurons.

Figure 3. A Model for Sympathetically Maintained Pain

(A) After acutely relieving pain by performing a sympathetic block, norepinephrine in
physiological concentrations was injected intra-dermally in a blinded fashion into the
previously hyperalgesic area. The norepinephrine injections into the affected, but not the
unaffected, extremity produced pain. Norepinephrine does not induce pain in control subjects.
These data suggest that the nociceptors are sensitized to catechols in patients with SMP
(adapted with permission [Ali et al., 2000]). ACUC, area under curve.
(B) In primates, normal nociceptors do not respond to catechol administration. However, in a
monkey-spinal nerve ligation model, nociceptors developed a response to the α 1 adrenergic
agonist phenylephrine administered topically to their receptive field (adapted and used with

permission [Ali et al., 1999]). AP, action potentials. (C) A model to account for SMP. After a
partial nerve lesion, some afferent fibers still remain in the skin. Factors released in the skin
induce the sympathetic efferents to sprout into more superficial areas of the skin (Yen et al.,
2006). These factors also lead the nociceptors to express α 1 adrenergic receptors. Now, the
release of norepinephrine from the sympathetic terminals leads to activation of the nociceptive
terminals, which accounts for the coupling of sympathetic activity with nociceptor responses.
Data are presented as mean ± SEM.

Figure 4. A Genetic Basis for Erythromelalgia

(A) Schematic of the Nav 1.7 voltage-gated sodium channel that is found exclusively in sensory
and sympathetic neurons. A number of point mutations have been identified in this sodium
channel in families of patients with erythromelalgia (Waxman and Dib-Hajj, 2005). The two
mutations shown here produced single amino acid substitutions at the sites indicated.
(B) Whole-cell-patch-clamp recordings in transfected HEK293 cells revealed that these point
mutations lead to an augmentation of the response of the channel to a slow depolarizing ramp
(100 mV in 500 ms). These mutations would be expected to increase the excitability of the
peripheral sensory neuron. (Adapted with permission [Cummins et al., 2004]. Copyright 2004
by the Society for Neuroscience.).

Figure 5. Central Sensitization Mechanisms Involved in the Spinal Nerve Ligation Model
Spontaneous activity from the injured afferents (L5) and intact nociceptors (L4) may sensitize
central pain-signaling neurons. The spontaneous activity in the L5 fibers is restricted to
myelinated afferents. Nociceptive C fibers from L4 spontaneously discharge and may
themselves be sensitized. The enhanced discharge of the primary afferents leads to augmented
response of dorsal horn cells to nociceptor input and increased synaptic efficacy of inputs from
mechanoreceptors (mechanism for allodynia). Alterations in descending modulation and
inhibitory interneuron function also likely play a role.

Figure 6.
Microglial Cells in the CNS Are Activated following Peripheral Nerve Injury and Release
Cytokines that Alter the Responses of Dorsal Horn Cells

Table 1
Examples of Neuropathic Pain Conditions
Disease Pathology Symptoms Hyperalgesia Special Features

Cooling Heat Mechanical
Traumatic neuropathy Axotomy distal to Ongoing pain ++ + ++ Great variety of

DRG presentations
Tic douloureux Compression (often Lightening- ? ? +++ Mechanical
vascular) of like attacks of stimuli evoke
trigeminal nerve near pain attacks of pain
brainstem
Painful diabetic neuropathy Length- Burning pain − + +/− Neuropathy
dependent neuropathy in the feet sometimes
affects small
fibers exclusively
Postherpetic neuralgia Results from damage Burning pain +/− +/− ++ Pain follows the
by herpes zoster distribution of the
infection of peripheral affected
nerve dermatomes

Mechanism of Neuropathic Pain

Uploaded by

Copyright:

Available Formats

Mechanism of Neuropathic Pain

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Mechanism of Neuropathic Pain

Uploaded by

Copyright:

Available Formats

NIH Public Access

Neuron. 2006 October 5; 52(1): 77–92.

Mechanisms of Neuropathic Pain

James N. Campbell1,* and Richard A. Meyer1

by the inability to detect a fine probe applied to the skin.

(Cook and Browder, 1965).

Nervous System Diseases Associated with Pain

Neuron. Author manuscript; available in PMC 2007 March 6.

Postherpetic neuralgia is a complication of shingles and is an example of how an infection can

Animal Models of Neuropathic Pain

Subsequent work indicated that an idiosyncratic immune-mediated response to the chromic

Neuron. Author manuscript; available in PMC 2007 March 6.

Though hyperalgesia is relatively easy to demonstrate in animal models, the measurement of

but that nonsteroidal drugs are in general not useful.

Secondary Hyperalgesia and Central Sensitization

Neuron. Author manuscript; available in PMC 2007 March 6.

Where Do the Abnormal Signals in Neuropathic Pain Originate?

Neuron. Author manuscript; available in PMC 2007 March 6.

A Role for Primary Afferents

pharmacological studies. For example, systemic administration of AM1241, a selective CB2

Systemic administration of artemin dose-dependently reversed the behavioral signs of

Antisense oligodeoxynucleotides (ODNs) directed against Nav 1.8 reversed signs of

The Injured Afferent Hypothesis

Neuron. Author manuscript; available in PMC 2007 March 6.

The Intact Nociceptor Hypothesis

Neuron. Author manuscript; available in PMC 2007 March 6.

Sympathetically Maintained Pain and the Intact Nociceptor Hypothesis

In a primate model of neuropathic pain, an L6 SNL leads to hyperalgesia just as it does in

The Role of Growth Factors

Neuron. Author manuscript; available in PMC 2007 March 6.

Transduction, Channel Function, and Ectopic Discharge

could account for this phenomenon.

Nociceptor sensitization could also relate to changes in voltage-gated sodium channels,

sodium-channel activation decreases, the response to a given generator potential will be

Neuron. Author manuscript; available in PMC 2007 March 6.

The Role of Central Sensitization

When it occurs as a result of inflammation, central sensitization is strongly dependent on

mechanisms is unlikely to be therapeutically beneficial.

Central sensitization involves homosynaptic and heterosynaptic mechanisms (Magerl et al.,

Neuron. Author manuscript; available in PMC 2007 March 6.

Ample evidence indicates that heterosynaptic and homosynaptic sensitization occur in

Homosynaptic and heterosynaptic sensitization involve many mechanisms, but fundamentally

receptors, including μ-opioid receptors, GABA-b, and adenosine receptors. Downregulation

Neurotransmitter release is triggered by voltage-gated calcium channel activity on the central

Neuron. Author manuscript; available in PMC 2007 March 6.

potential mechanism for sensitization of dorsal horn neurons.

Another possible mechanism of postsynaptic sensitization involves an increased trafficking of

(Tomiyama et al., 2005).

Role of Disinhibition Mechanisms

Neuron. Author manuscript; available in PMC 2007 March 6.

Descending Modulatory Mechanisms

The Immune System and Neuropathic Pain

in approaching the question of immune mechanisms.

Peripheral Immune Mechanisms

Neuron. Author manuscript; available in PMC 2007 March 6.

Central Immune Mechanisms

Neuron. Author manuscript; available in PMC 2007 March 6.

Sodium-channel dysfunction likely plays an important role in leading to ectopic generation of

Neuron. Author manuscript; available in PMC 2007 March 6.

of the sensory abnormalities. Pain 1989;37:173–185. [PubMed: 2748190]