1Pain Research, Department of Anaesthetics, Imperial College School of Medicine, Chelsea and Westminster Hospital Campus, London W2 1NY, UK. 2Novartis Institute for Medical Sciences, 5 Gower Place, London, WC1, UK. 3Centre for Neuroscience Research, Kings College London, Guys Hospital, London, UK*Corresponding author: Department of Anaesthetics, Imperial College School of Medicine, Chelsea and Westminster Hospital Campus, 369 Fulham Road, London SW10 9NH, UK
![]() |
Abstract |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Keywords: pain, neuropathic
![]() |
Introduction |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
![]() |
Animal models |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
With these caveats in mind, we must first survey the various animal models of neuropathic pain that have been developed, with simple axotomy being the first widely used model.138 In this model, the self-mutilation of the injured foot (autotomy) was often observed and interpreted as a response to pain, the authors suggesting an afferent barrage from the neuroma as being crucial in generating autotomy behaviour. More recently, it has been suggested that autotomy occurs in response to the total motor and sensory denervation of the hind-paw rather than pain (for review see63). Ethical considerations dictate that autotomy is undesirable as an outcome measure and it is a very rare occurrence with the more recent neuropathic models.
The majority of currently used neuropathic pain models share alterations in hind-limb cutaneous sensory thresholds following partial injury of a peripheral (usually sciatic) nerve as a common feature. In particular, demonstration of hyperalgesia to noxious thermal stimuli and allodynia to cold and mechanical stimuli are used as outcome measures. The three most commonly used models are the chronic constriction injury (CCI) of sciatic nerve,10 the partial sciatic nerve ligation model (PNL)116 and the spinal nerve ligation model (SNL)66 (Figure 2).
|
A direct comparison of these three models has been reported.65 In this study, the authors demonstrated a similar onset of sensory threshold changes in mechanical and cold allodynia in all three models, but a greater magnitude of change in sensory thresholds in SNL. All three models demonstrated significant cold and mechanical allodynia at 3 days after injury and spontaneous pain at one day after injury. Mechanical allodynia was determined by the application of an 8.4 mN Von Frey hair. The allodynia was greatest in the SNL model with an 80% response frequency, followed by PNL (
60% response frequency) and CCI (
45% response frequency). They also demonstrated a more significant involvement of the sympathetic nervous system component in the sensory response to SNL than following PNL or CCI.
A more recent development of the hind-limb peripheral nerve injury models has been a description of the sequelae of injury to the terminal branches of the sciatic nerve. Decosterd and Woolf described a spared nerve injury model involving tight ligation and lesion of the tibial and common peroneal nerves, leading to robust sensory threshold changes to mechanical, thermal, and cold stimuli.28 Further studies investigated more closely the importance of injury to each branch in the development of behavioural signs of neuropathy, namely mechanical and cold allodynia and spontaneous pain.75 This study demonstrated that the largest change in sensory thresholds was initiated by injury to the tibial and sural nerves, leaving the common peroneal nerve intact. This model allows testing of distinct regions of the hind-paw which are either innervated by injured or uninjured neurones, as well as separating degenerating neurones from uninjured neurones to a greater level. A further model exploiting injury to the sciatic nerve is a photochemical/laser irradiation model. The sciatic nerve is subjected to an ischaemic injury as a result of laser activation of a systemically administered photosensitive dye resulting in a thrombosis within the nerve because of a photochemical reaction. This model was originally described for the study of direct spinal cord injury150 before being adapted to become a peripheral nerve injury model.73 This model has been described as having good reproducibility statistics, as well as a quantifiable degree of nerve injury. However, this model has not been widely adopted, presumably because of the expenses of lasers.
The majority of animal models of neuropathy have been based on a discrete peripheral nerve injury. However, some have been developed to more closely mimic individual disease states. An example of this is the streptozotocin model of peripheral diabetic neuropathy.85 In this model, a single injection of streptozotocin induces diabetes and then hyperalgesia and allodynia. This model has been used extensively in the testing of new pharmaceuticals such as gabapentin,41 however, the influence of the ill health of the rats per se (as opposed to neuropathy) on sensory thresholds has been questioned.45 A further example, described by Idanpaan-Heikkila and Guilbaud, uses a CCI of the infraorbital branch of the trigeminal nerve as a model for trigeminal neuralgia.58 A model of acute herpes zoster has been reported, which may offer some insight into the mechanism of acute zoster pain and possibly post-herpetic neuralgia.42 Takasaki and colleagues have also demonstrated that, in comparison with herpes simplex in humans, herpes simplex virus type-1 induces allodynia and hyperalgesia in infected rats.128
The majority of neuropathic pain models were originally described in rats, but more recently the PNL model has been adapted to the mouse,86 as has the photochemically induced ischaemia model.51 The translation of these models from rat to mouse is important as novel transgenic tools, useful for the study of neuropathic pain, are developed further. However, mice are not merely small rats and often respond in a quantitatively and qualitatively different manner to an insult, and the translation of pain models from rats to mice is more than simply an adaptation of surgical techniques. Other developments in genetics could be exploited to enhance understanding of painful neuropathy. For example, one such approach described the induction of mutants identified in inherited peripheral neuropathies into mice.89
![]() |
Mechanisms of neuropathic pain |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
|
|
These observations suggest that the development of ectopic activity may be particularly important for the development of hyperalgesia, allodynia and ongoing pain associated with nerve injury. Clinical observations suggest that ectopic activity is responsible for ongoing neuropathic pain.49 It is now recognized that two populations of afferent fibres develop ectopic activity following nerve injury, the injured sensory neurones themselves and their uninjured neighbours.48 To what degree each population is responsible for the maintenance or initiation of neuropathic pain is currently under debate. Support for a major role of injured afferents comes from the work of Sheen and Chung117 who used the SNL model of neuropathic pain, ligation of the L5 and L6 spinal nerves. They reported that cutting the dorsal roots of injured segments eliminated pain behaviours. Three other recent studies have demonstrated a direct correlation in the time course of behavioural changes following spinal nerve injury with that of ectopic activity in A-fibres that gives support to the injured afferent hypothesis.67 82 83 Note that changes in ectopic C-fibre activity only occur 34 weeks following axotomy and may persist for many weeks following injury.31
Evidence has also been obtained that signals in uninjured neighbouring afferents have a role in the development of neuropathic pain behaviours. Using a modified spinal SNL model, Yoon and colleagues154 and Li and co-workers80 showed that an L4 rhizotomy would abolish pain behaviours evoked by L5 SNL. This suggests that the signals involved in pathological nociception arise from the intact neurones. It is important to bear in mind, therefore, that pain arising as a result of peripheral nerve damage may reflect activity in both damaged as well as intact sensory neurones.
Sodium channels are critical to the physiology of excitable membranes, including neuronal membranes. One important finding of potential significance to the generation of ectopic firing is alterations in the expression of sodium channels in the cell bodies and the terminal neuroma of peripheral nerves following nerve injury (summarized in Table 2). In 1989, Devor and colleagues demonstrated the accumulation of Na+ channels in the neuroma of cut sensory axons32 and then demonstrated that the Na+ channels were the cause of ectopic discharge.90 However, molecular biology has since revealed that are many different and distinct voltage-gated Na+ channels, of which at least six are expressed on the cell bodies of primary afferent neurones within the DRG.141 These can be further split into tetrodotoxin (TTX)-sensitive and TTX-resistant sub-types. TTX-sensitive channels are expressed throughout the central nervous system, and predominantly in A-fibres within the DRG. TTX-resistant channels are found only within a subset of primary afferent neurones of the DRG, specifically in the smaller C-fibres associated with nociception.2 Following peripheral nerve injury, it has been demonstrated that there is a re-organization of the nature and levels of expression of the various channels.142 The expression of some sodium channels sub-types in DRG cell bodies is diminished following nerve injury, whilst others appear de novo and others translocate to different parts of the neurone. More specifically, there is an up-regulation of type III TTX-sensitive channel gene expression (these are not normally expressed by DRG cells),142 and a down-regulation of SNS (aka PN3) and NaN (aka SNS2) TTX-resistant channels gene expression.36 This has been demonstrated to occur both after axotomy36 142 and after CCI with a 40% decrease in SNS and NaN mRNA after CCI.37 The SNS channel expression appears to translocate from the cell body to the neuroma, which may explain the hypersensitivity of the neuroma. These findings were corroborated in an immunohistochemical study (for NaN and SNS) of tissue taken from patients suffering from chronic neuropathic pain after traumatic brachial plexus avulsion.24 Another study investigated the changes in SNS/PN3 and SNS2/NaN TTX-resistant Na+ channels in injured human sensory nerves.153 This demonstrated degradation products of the SNS2/NaN and an increase in SNS/PN3 expression in injured nerves localized close to the injury site and within the neuroma.
|
The mechanism contributing to the changes in Na+ channel expression in peripheral nerve injury is unclear, but neurotrophin supply appears to be a crucial factor. It has been shown that DRG neurones in culture will increase expression of type III channel expression and decrease SNS channel expression in the absence of NGF.13 NaN channel expression is similarly reliant on another growth factor, for example, glial-derived neurotrophic factor (GDNF). It seems clear that the decrease in SNS2/NaN expression, the relocation of SNS/PN3 channel expression and the de novo synthesis of type III channels are central in the spontaneous generation of action potentials. These changes in DRG following peripheral nerve injury suggest a contribution to neuronal hyperexcitability from sodium channels and this Na+ channel-induced hyperexcitability is likely to manifest itself as an increase in ectopic firing, because of the rapid repriming and lower resting thresholds. It is likely that the rapidly repriming, normally silent, type III TTX-sensitive channel has a significant role to play in this, and this is supported by low dose TTX studies. Omana-Zapata and colleagues demonstrated in axotomized rats that i.v. TTX produced dose-dependent inhibition of ectopic activity.100 Similarly, Lyu and colleagues demonstrated that topically applied, at the DRG level, sub-action potential blocking levels of TTX reduced mechanical allodynia in the SNL model.84 The sodium channel blocker lidocaine has also been demonstrated to be of some benefit in neuropathic pain treatment,8 but currently available sodium channel blockers do not, by and large, discriminate between the different types of channel and are, therefore, associated with potentially lethal side-effects. Tailoring novel compounds to specifically act at the sodium channels implicated in neuropathic pain may represent a significant therapeutic advance.
Sodium channels are not the only voltage-gated channels, which are altered following peripheral nerve injury. Calcium channels have also been shown to influence the generation of hyperalgesia and allodynia. Specific antagonists for neuronal N-type Ca2+ channels have been shown to reduce heat hyperalgesia and mechanical allodynia in the CCI model when administered directly to the site of nerve injury.149 Further studies then demonstrated that subcutaneous administration of an N-type, but not P- or Q-type, Ca2+ channel antagonist attenuated mechanical hyperalgesia in the PNL model of neuropathic pain, suggesting a local effect of N-type Ca2+ channels in the generation of hyperalgesia.143 This alteration of Ca2+currents after peripheral nerve injury has also been demonstrated electrophysiologically.7 More specifically, N-type current measured in the DRG was seen to decrease after axotomy, with no significant change in P- or Q-type currents. Cannabinoids CB1 receptor agonist attenuate Ca2+ flux at N-type channels103 and we have recently demonstrated that the synthetic cannabinoid Win 55,2122 attenuates thermal hyperalgesia and mechanical and cold allodynia in the SNL model of painful neuropathy via the CB1 receptor.15 Furthermore, the anti-convulsant gabapentin binds to the 2
sub-unit of calcium channels46 130 and is effective in relieving allodynia and hyperalgesia in animal models and neuropathic pain in man.1 101 113
The changes in both Na+ and Ca2+ channels detailed above are important in neuropathic pain. The de novo synthesis of rapidly repriming III channels, down-regulation of TTX-resistant Na+ channels and loss of high-voltage activated N-type Ca2+ channels seen in response to peripheral nerve injury, increases the excitability of the neurones. This in turn will lead to an increase in firing susceptibility and frequency, possibly resulting in not only spontaneous pain, but also central sensitization as discussed later.
Collateral sprouting
Sprouting of collateral fibres from sensory axons in the skin into denervated areas has been described following nerve crush injuries.33 Sprouting was also observed from the saphenous nerve in the CCI model.111 This sprouting occurred at around 10 days post-operation, but the degree of sprouting was not proportional to the degree of hyperalgesia after chronic sciatic section.68 These results indicate that collateral sprouting is unlikely to contribute significantly to the pain behaviour seen in this model. The sprouting was effectively blocked by the administration of anti-NGF35 and it is, therefore, likely that a local release of NGF from sources within the skin (keratinocyte, immune cells) is responsible for axon sprouting under these circumstances.
Coupling between the sympathetic nervous system and the sensory nervous system
Clinicians have observed for many years that in a small subset of patients suffering from neuropathic pain, the pain is somewhat dependent on activity in the sympathetic nervous system. This is often referred to as sympathetically maintained pain and, for example, some patients suffering from complex regional pain syndrome type 1 (CRPS1) can be classified as having sympathetically maintained pain. It has recently been demonstrated that an abnormal contact develops between the sympathetic nervous system and the sensory nervous system following peripheral nerve injury, which may underlie the enhanced sensitivity to catecholamines which some patients with neuropathic pain develop.61 The key question is how and where does the sympathetic nervous system become coupled to the sensory nervous system to produce the pain observed in the clinical situation? The basic observation must be that activity in the sympathetic nervous system initiates abnormal impulse traffic in sensory neurones that leads to pain perception. Several sites of coupling between sensory and sympathetic nervous systems have been proposed and tested in animal models. The following have received experimental support.
1. Direct chemical coupling within peripheral effector sites between the noradrenergic and sensory neurone terminals.102
2. Ephaptic nerve coupling. Observed between sensory fibres in a damaged nerve but not so far between sympathetic and sensory fibres.14
3. Indirect coupling via peripheral sensitizing mechanisms involving the release of inflammatory mediators from sympathetic terminals and the sensitization of primary sensory neurone axons.78
4. Direct coupling between the sympathetic nervous system and the sensory nervous system in the dorsal root ganglion.
This latter possibility has received much attention recently with numerous studies demonstrating that peripheral nerve injury leads to sympathetic sprouting in the DRG (Fig. 4). McLachlan and colleagues described sprouting of noradrenergic perivascular sympathetic axons into the DRG following ligation of the sciatic nerve.91 These axons were observed to form baskets around the large diameter neurones, leading to the possibility of sympathetic input being able to activate the neurones. Sympathetic sprouting has also been demonstrated following SNL19 and CCI108 models. In the McLachlan study, onset of sprouting occurred around 21 days after nerve injury, whereas Chung and others described visualization of sympathetic sprouts after 3 days which was maintained for up to 20 days before declining gradually.20 It should be noted that onset of behavioural signs of neuropathy in SNL are developed by 3 days post-surgery. This study also demonstrated elimination of the majority of sprouting following sympathectomy, confirming that the sprouts were sympathetic post- ganglionic fibres. A direct comparison of the sympathetic sprouting in CCI, PNL, and SNL was performed76 and demonstrated a similar pattern of sprouting in CCI and PNL, with an onset after 2 weeks, but a more rapid onset of within 1 week of SNL.
The mechanism for onset of the sympathetic sprouting is unclear. It is likely, however, that neurotrophic factors and cytokines linked to Wallerian degeneration are crucial to the process. Wallerian degeneration results in an increase of a large variety of cytokines and growth factors in the local milieu. Thompson and Majithia demonstrated the ability of the cytokine leukaemia inhibitory factor (LIF) to stimulate sympathetic sprouting, akin to that seen in peripheral nerve injury, in non-nerve injured animals.132 In previous studies, the neurotrophin nerve growth factor (NGF) has been demonstrated as being able to induce sympathetic sprouting in the CNS59 and this led to the investigation of the role of NGF, and GDNF, in sympathetic sprouting in DRG.62 This study demonstrated that exogenously applied NGF, but not GDNF, to uninjured rats resulted in sympathetic sprouting reminiscent of that in CCI rats. Also demonstrated, was that sequestration of endogenous NGF at the injury site did not reduce sprouting. This suggests a mechanism of sprouting involving the direct action of NGF at the level of the DRG, a theory supported by raised NGF mRNA levels in the DRG following sciatic nerve injury.115 These studies have proposed some potential mechanisms for sympathetic sprouting in the DRG (see109 for review).
Sprouting has been described in many animal models of peripheral nerve injury, but what are the consequences of such sprouting? The terminals of the sprouted neurones have been shown to form functional synapse-like structures with the cell bodies.91 These structures could be involved in the formation and maintenance of abnormal excitation arising from the DRG, a hypothesis supported by electrophysiological studies in which sympathetic stimulation increased sensory ectopic discharge from the DRG.31 As both sympathectomy118 and guanethidine,98 a noradrenergic depleting agent, have been demonstrated to relieve hyperalgesia in peripheral neuropathy models, it is fair to assume that these functional interactions have some importance in the sympathetically maintained pain sub-groups of neuropathic pain patients. Sympathetic blocks have been used in treatment of neuropathic pain,148 although adequately controlled data are not available to help fully determine the efficacy of this approach. With the time-scale of sprouting corresponding with the onset of behavioural signs of both hyperalgesia and allodynia, block of the input from these fibres, or more difficultly, prevention of sprouting has potential to reduce sympathetically maintained pain in neuropathic patients.
Bradykinin
There is an alteration in expression of bradykinin binding sites within dorsal root ganglion neurones after axotomy.104 Bradykinin has been shown to play an important role in the hyperalgesia associated with inflammatory pain states.39 60 Petersen and colleagues showed an increase in bradykinin binding sites at 2 days post-axotomy, suggesting a potential role for bradykinin antagonists in the treatment of neuropathic pain, specifically to combat hyperalgesia.104
Central mechanisms
Spinal cordanatomical re-organization
There is a considerable degree of re-organization of spinal cord in response to peripheral nerve injury (Fig. 5). Under normal physiological conditions, different classes of primary afferent neurone fibres terminate in specific laminae of the dorsal horn. As a generalization, the nociceptive small diameter cells with myelinated A-fibres and unmyelinated C-fibres terminate in the superficial laminae (I and II) of the dorsal horn whilst the large diameter neurones with myelinated Aß-fibres terminate in laminas III and IV. Lamina V is a region of convergence of inputs. Woolf and colleagues demonstrated that after sciatic nerve axotomy, the central terminals of the large myelinated primary afferent neurones sprouted into lamina II of the superficial horn.146 Koerber and colleagues also showed a sprouting of Aß-fibres into lamina II of the superficial dorsal horn after peripheral axotomy.69 Woolf and co-workers then demonstrated that this sprouting occurred within 1 week post-axotomy, was at its highest 2 weeks post-axotomy and persisted over 6 months post-axotomy.147 The authors also demonstrated that this sprouting persisted beyond periods of peripheral nerve regeneration. One consequence of this synaptic rearrangement is that second-order neurones within the spinal cord, that normally receive predominantly high-threshold sensory input, begin to receive inputs from low-threshold mechanoreceptors. This misinterpretation of information within the spinal cord may result in low-threshold sensory information being interpreted as nociceptive, thus, providing another explanation for the emergence of allodynia after peripheral nerve injury.
|
The functional significance of this sprouting needs to be considered. C-fibres normally innervate lamina II and are responsible for nociceptive signalling, whilst Aß-fibres are large fast conducting neurones that sub-serve low-threshold non-noxious inputs. Therefore, if the Aß-fibres sprout into lamina II, and establish functional synaptic contact with second-order neurones, then low-threshold non-noxious inputs from the Aß-fibres can be interpreted as nociceptive in origin. This would be a plausible explanation for allodynia, a hypothesis supported by electrophysiological data: recordings from dorsal horn neurones in a rat transverse spinal cord slice were examined. In normal rats, lamina II cells exhibited long-latency responses to high-threshold nerve stimulation. However, after sciatic nerve section, and subsequent sprouting of Aß-fibres into lamina II, 54% of the activity in lamina II were initiated by low-threshold stimulation and the majority exhibited short-latency responses reminiscent of those in lamina III of normal rats.70 However, it should be noted that optimal sprouting does not occur until 2 weeks post-injury and so cannot be solely responsible for the allodynia observed in neuropathy models.
Spinal cordhyperexcitability
In a similar fashion to persistent inflammation, the afferent barrage associated with peripheral nerve injury is associated with the development of a sustained state of hyperexcitability of dorsal horn neurones, a process dubbed central sensitization.21 136 In addition to events such as lowering of activation thresholds of spinal neurones, central sensitization is characterized by the appearance of wind-up.93 140 (For review see38.) Wind-up is characterized by an increasing response to repeated C-fibre volleys, and may contribute to hyperalgesia. However, the exact relationship of the relatively short lived phenomenon of wind-up and the persistent state of central sensitization remains to be fully elucidated.79 144 Electrophysiological data demonstrated that about 90% of dorsal horn neurones studied in the lumbar enlargement of the spinal cord exhibited abnormal characteristics after CCI.74
Study of the pharmacology of central sensitization may open the door for novel analgesics effective in neuropathic pain. The excitatory amino acid glutamate is the major excitatory neurotransmitter released at the central terminals of primary afferent nociceptive neurones after noxious stimulation. Whilst glutamate acts at a number of post-synaptic receptors, a large body of evidence suggests that the ionotropic NMDA sub-type is the most intimately involved in both inflammation and nerve injury-induced central sensitization (see38). Removal of an Mg2+ dependent ion channel block and receptor phosphorylation are critical events in activating the NMDA receptor so that glutamate is able to exert its effects. NK1 (substance P), AMPA (glutamate), and trkB (BDNF) receptors are all involved in this permissive process.131
A number of lines of evidence suggest that NMDA receptor antagonists may have a role in attenuating features of neuropathic pain. First, glutamate concentration increases in the ipsilateral dorsal horn after CCI.64 Davar and colleagues described the prevention of hyperalgesia development in the CCI model by continual pre- and post-injury i.p. administration of the NMDA receptor antagonist MK-801.27 Mao and others described a reduction in hyperalgesia in the same model at a lower dose of MK-801 and also demonstrated the dose-dependent anti-hyperalgesic effect of intrathecally administered MK-801 3 days post-injury.88 Electrophysiological data also demonstrates that MK-801 significantly reduces the hyper-responsiveness to noxious stimulation after peripheral nerve injury.123 Interestingly, the authors found that MK-801 had no effect on the frequency of ectopic baseline firing (spontaneous pain), suggesting that this is not mediated through central NMDA receptors.
Glycine is recognized as a modulator of the agonist action of glutamate at the NMDA receptor.23 This has led to investigation of the anti-nociceptive effects of antagonists to the glycine modulatory site of the NMDA receptor. Quartaroli and colleagues described the efficacy of a glycine site antagonist in preventing the development of hyperalgesia in the CCI model and attenuating wind-up in isolated spinal cord neurones.106 Co-administration of a glycine/NMDA receptor antagonist and morphine has also been demonstrated to attenuate pain behaviour in an animal model of trigeminal neuralgia.18 In human neuropathic pain, ketamine, an NMDA receptor antagonist has been used to successfully treat neuropathic pain in some patients,107 suggesting a place in therapy for NMDA antagonists and an area in which more investigation should be performed.
The mechanism by which NMDA receptors contribute to maintenance of central sensitization should also be discussed. After peripheral neuropathy, both an increase in excitatory amino acids and [Ca2+]i were observed to occur in an NMDA receptor dependent manner.64 This suggests that initial NMDA receptor activation contributes to the increased levels of glutamate and aspartate, representing a continual positive feedback loop which maintains sensitization. The increased [Ca2+]i could also form a positive feedback loop, potentially through indirect activation of protein kinase C (PKC), a hypothesis supported by the anti-allodynic effect of a PKC inhibitor in the SNL model of neuropathic pain.56
The -aminobutyric acid (GABA) pathway forms a major inhibitory neurotransmitter system in the CNS. Suppression of this pathway by the GABAA receptor antagonist bicuculline is associated with a dose-dependent allodynia152 and GABA receptor levels in the spinal cord are decreased within 2 weeks of sciatic nerve axotomy,17 probably as a result of degeneration of the primary afferent neurone terminals on which the receptor is localized.16 This suggests a role for GABA in modulating the response to peripheral nerve injury, and Sivilotti and Woolf hypothesized that central sensitization might be contributed to by a decrease in the efficacy of GABA pathways.120 The GABAB agonist baclofen is anti-nociceptive in naïve animals, but its potency increases 3-fold in the CCI model of neuropathic pain.121 More recently, Hwang and Yaksh demonstrated a dose-dependent attenuation of SNL associated allodynia, mediated via both GABAA and GABAB receptors, after intrathecal administration of GABA receptor agonists.57 Stiller and colleagues were able to measure the concentration of extracellular GABA concentrations in normal and nerve injured rats and established a significant decrease in extracellular GABA concentrations in the nerve injured rats exhibiting allodynia, but a much smaller decrease in non-allodynic rats.126 They then demonstrated that spinal cord stimulation, a potential therapy in humans, increased the levels of GABA in allodynic rats and that this in turn attenuated the release of EAAs in the dorsal horn.25 These studies again indicate a role for decreased efficacy of GABA pathways in neuropathic allodynia.
A separate inhibitory pathway in the CNS is that of the purinergic system, including specifically adenosine. Adenosine exhibits both pre-114 and post-synaptic actions and could produce anti-nociception by indirect interaction with EAA release.22 Levels of circulating adenosine within the blood and CSF of neuropathic, non-neuropathic nerve lesioned and control humans were compared.50 This study reported a significant decrease in circulating blood and CSF adenosine concentrations in neuropathic patients. From these data, coupled with the effective attenuation of neuropathic pain seen after low-dose infusion of adenosine in a preliminary study,122 a role of adenosine in modulating the development of neuropathic pain is a possibility.
Thus, there is evidence that a combination of increased activity in the excitatory and a concomitant decrease of activity in inhibitory systems within the spinal cord contributes to the phenomenon of central sensitization after peripheral nerve injury.
Endogenous opioid and cannabinoid systems
It is generally accepted that opioids are less effective in relieving neuropathic pain than inflammatory pain.30 112 Although, the exact extent of this is controversial, the balance of evidence supports the view of an unfavourable (right) shift in the dose response function for opioids in neuropathy. There are a number of plausible explanations for this observation, including a loss of peripheral opioid effects, loss of spinal opioid receptors and increased activity in physiological opioid antagonists systems (Fig. 6).
|
In the spinal cord, opioid-receptors are localized predominantly on the pre-synaptic terminals of primary afferents in the superficial dorsal horn.11 However, after peripheral axotomy, a decrease in immunocytochemical receptor staining has been reported29 155 and also after dorsal rhizotomy,53 neonatal C-fibre degradation54 and CCI12 a decrease in µ-opioid receptor binding is observed, presumably reflecting the degeneration of primary afferent neurones as discussed above. However, in the SNL model, intrathecal administration of morphine produced greater inhibition of noxious stimuli generated electrophysiological responses than systemically administered morphine.127 This suggests a potential role of spinally administered morphine where systemic morphine and other approaches have failed. Conversely, separate studies have demonstrated, immunocytochemically, an increase in µ-opioid receptors in the ipsilateral dorsal horn after CCI injury and a decrease after tight ligation of the sciatic nerve47 whilst SNL injury caused little change in µ-opioid receptor binding or expression.105
As mentioned above, there is an increased expression of the endogenous opioid antagonist CCK mRNA after peripheral nerve injury. A corresponding increase in CCKB receptor staining in the superficial dorsal horn has also been observed after peripheral axotomy. This appears to be related to increased synthesis of the receptor in the DRG which is then transported to the primary afferent central terminals the spinal cord.6 It is possible that this increased level of inhibition on the opioid system contributes to decreased potency of opioids in neuropathic pain. This hypothesis was supported by a recent study in which morphine potency was enhanced in the SNL model by co-administration with a CCKB receptor antagonist.71
Finally, recent advances in the understanding of cannabinoid analgesia55 103 appear to indicate a therapeutic advantage of cannabinoids over opioids in the management of painful neuropathy (Fig. 7). Cannabinoid CB1 are located in areas of the spinal dorsal intimately associated with nociception.40 In contrast, to the situation for spinal opioid receptors described above, no biologically relevant decrease in CB1 receptor immunostaining was evident after dorsal rhizotomy suggesting a relative sparing of CB1 receptors, compared with opioid receptors, after peripheral nerve injury40 (Fig. 6). Similarly, using an alternative experimental approach, in which neonatal capsaicin treatment was used to deplete primary afferent C-fibres, Hohmann and Herkenham demonstrated only a modest decrease (16%) of cannabinoid receptor binding in the superficial dorsal horn.54 Meanwhile, µ-opioid receptor binding was considerably decreased (
60%) in the same region. In behavioural studies, cannabinoids have been shown to attenuate the sensory changes associated with CCI and SNL.15 52
|
![]() |
Conclusion |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
Eventually, it may be possible to improve the ethos of clinical management protocols so that there will be a move away from the current disease based treatment towards symptom or, ultimately, mechanism based therapies, as suggested by Woolf and Mannion.145 It is a clinical challenge to determine which mechanisms may be operating and hence responsible for individual symptomology in each patient. However, whilst a symptom-based approach is feasible it remains largely unevaluated in the clinic. Mechanism based therapy will require a better understanding of mechanisms involved in neuropathic pain and reliable convenient tools for their assessment in the clinic. Advances in our understanding of genetics may uncover genetic variation in the susceptibility of individuals to develop neuropathic pain after a nerve injury96 97 and genetically tailor analgesics based on an individuals pharmacogenetic profile.95
![]() |
Note added in proof |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
1 Hudson LJ, Bevan SJ, Wotherspoon G, Gentry GC, Fox A, Winter J. VR-1 protein expression increases in undamaged DRG neurons after partial nerve injury. Eur J Neurosci (in press).
![]() |
References |
---|
![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2 Akopian AN, Sivilotti L, Wood JN. A tetrodotoxin-resistant voltage-gated sodium channel expressed by sensory neurons. Nature 1996; 379: 25762[ISI][Medline]
3 Amir R, Devor M. Chemically mediated cross-excitation in rat dorsal root ganglia. J Neurosci 1996; 16: 473341
4 Amir R, Devor M. Functional cross-excitation between afferent A- and C-neurons in dorsal root ganglia. Neuroscience 2000; 95: 18995[ISI][Medline]
5 Amir R, Michaelis M, Devor M. Membrane potential oscillations in dorsal root ganglion neurons: role in normal electrogenesis and neuropathic pain. J Neurosci 1999; 19: 858996
6 Antunes Bras JM, Laporte A, Benoliel JJ, et al. Effects of peripheral axotomy on cholecystokinin neurotransmission in the rat spinal cord. J Neurochem 1999; 72: 85867[ISI][Medline]
7 Baccei ML, Kocsis JD. Voltage-gated calcium currents in axotomised adult rat cutaneous afferent neurons. J Neurophysiol 2000; 83: 222738
8 Bach FW, Jensen TS, Kastrup J, Stigsby B, Dejgard A. The effect of intravenous lidocaine on nociceptive processing in diabetic neuropathy. Pain 1990; 40: 2934[ISI][Medline]
9 Bennett DL, French J, Priestley JV, McMahon SB. NGF but not NT-3 or BDNF prevents the A-fiber sprouting into lamina II of the spinal cord that occurs following axotomy. Mol Cell Neurosci 1996; 8: 21120[ISI][Medline]
10 Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988; 33: 87107[ISI][Medline]
11 Besse D, Lombard MC, Besson JM. Autoradiographic distribution of mu, delta and kappa opioid binding sites in the superficial dorsal horn, over the rostrocaudal axis of the rat spinal cord. Brain Res 1991; 548: 28791[ISI][Medline]
12 Besse D, Lombard MC, Perrot S, Besson JM. Regulation of opioid binding sites in the superficial dorsal horn of the rat spinal cord following loose ligation of the sciatic nerve: comparison with sciatic nerve section and lumbar dorsal rhizotomy. Neuroscience 1992; 50: 92133[ISI][Medline]
13 Black JA, Langworthy K, Hinson AW, Dib Hajj SD, Waxman SG. NGF has opposing effects on Na+ channel III and SNS gene expression in spinal sensory neurons. Neuroreport 1997; 8: 23315[ISI][Medline]
14 Blumberg H, Janig W. Activation of fibres via experimentally produced stump neuromas of skin nerve: ephaptic transmission or retrograde sprouting? Exp Neurol 1982; 76: 46882[ISI][Medline]
15 Bridges D, Ahmad KS and Rice ASCR. The cannabinoid WIN 55,2122 attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Symposium on the Cannabinoids, International Cannabinoid Research Society; 2000: 117
16 Castro Lopes JM, Malcangio M, Pan BH, Bowery NG. Complex changes of GABAA and GABAB receptor binding in the spinal cord dorsal horn following peripheral inflammation or neurectomy. Brain Res 1995; 679: 28997[ISI][Medline]
17 Castro Lopes JM, Tavares I, Coimbra A. GABA decreases in the spinal cord dorsal horn after peripheral neurectomy. Brain Res 1993; 620: 28791[ISI][Medline]
18 Christensen D, Gautron M, Guilbaud G, Kayser V. Combined systemic administration of the glycine/NMDA receptor antagonist, (+)-HA966 and morphine attenuates pain-related behaviour in a rat model of trigeminal neuropathic pain. Pain 1999; 83: 43340[ISI][Medline]
19 Chung K, Kim HJ, Na HS, Park MJ, Chung JM. Abnormalities of sympathetic innervation in the area of an injured peripheral nerve in a rat model of neuropathic pain. Neurosci Lett 1993; 162: 858[ISI][Medline]
20 Chung K, Lee BH, Yoon YW, Chung JM. Sympathetic sprouting in the dorsal root ganglia of the injured peripheral nerve in a rat neuropathic pain model. J Comp Neurol 1998; 376: 24152
21 Coderre TJ, Katz J, Vaccarino AL, Melzack R. Contribution of central neuroplasticity to pathological pain: review of clinical and experimental evidence. Pain 1993; 52: 25985[ISI][Medline]
22 Corradetti R, Lo Conte G, Moroni F, Passani MB, Pepeu G. Adenosine decreases aspartate and glutamate release from rat hippocampal slices. Eur J Pharmacol 1984; 104: 1926[ISI][Medline]
23 Corsi M, Fina P, Trist DG. Co-agonism in drug-receptor interaction: illustrated by the NMDA receptors. Trends Pharmacol Sci 1996; 17: 2202[ISI][Medline]
24 Coward K, Plumpton C, Facer P, et al. Immunolocalization of SNS/PN3 and NaN/SNS2 sodium channels in human pain states. Pain 2000; 85: 4150[ISI][Medline]
25 Cui JG, OConnor WT, Ungerstedt U, Linderoth B, Meyerson BA. Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino acids in mononeuropathy via a GABAergic mechanism. Pain 1997; 73: 8795[ISI][Medline]
26 Cummins TR, Waxman SG. Downregulation of tetrodotoxin-resistant sodium currents and upregulation of a rapidly repriming tetrodotoxin-sensitive sodium current in small spinal sensory neurons after nerve injury. J Neurosci 1997; 17: 350314
27 Davar G, Hama A, Deykin A, Vos B, Maciewicz R. MK-801 blocks the development of thermal hyperalgesia in a rat model of experimental painful neuropathy. Brain Res 1991; 553: 32730[ISI][Medline]
28 Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000; 87: 14958[ISI][Medline]
29 deGroot JF, Coggeshall RE, Carlton SM. The reorganization of mu opioid receptors in the rat dorsal horn following peripheral axotomy. Neurosci Lett 1997; 233: 1136[ISI][Medline]
30 Dellemijn P. Are opioids effective in relieving neuropathic pain? Pain 1999; 80: 45362[ISI][Medline]
31 Devor M, Janig W, Michaelis M. Modulation of activity in dorsal root ganglion neurons by sympathetic activation in nerve-injured rats. J Neurophysiol 1994; 71: 3847
32 Devor M, Keller CH, Deerinck TJ, Levinson SR, Ellisman MH. Na+ channel accumulation on axolemma of afferent endings in nerve end neuromas in Apteronotus. Neurosci Lett 1989; 102: 14954[ISI][Medline]
33 Devor M, Schonfeld D, Seltzer Z, Wall PD. Two modes of cutaneous reinnervation following peripheral nerve injury. J Comp Neurol 1979; 185: 21120[ISI][Medline]
34 Devor M, Wall PD. Cross-excitation in dorsal root ganglia of nerve-injured and intact rats. J Neurophysiol 1990; 64: 173346
35 Diamond J, Holmes M, Coughlin M. Endogenous NGF and nerve impulses regulate the collateral sprouting of sensory axons in the skin of the adult rat. J Neurosci 1992; 12: 145466[Abstract]
36 Dib Hajj S, Black JA, Felts P, Waxman SG. Down-regulation of transcripts for Na channel alpha-SNS in spinal sensory neurons following axotomy. Proc Natl Acad Sci USA 1996; 93: 149504
37 Dib Hajj SD, Fjell J, Cummins TR, et al. Plasticity of sodium channel expression in DRG neurons in the chronic constriction injury model of neuropathic pain. Pain 1999; 83: 591600[ISI][Medline]
38 Doubell TP, Mannion RJ, Woolf CJ. The dorsal horn: State-dependent sensory processing, plasticity and the generation of pain. In: Wall PD, Melzack R, eds. Textbook of Pain, 4th edn. London: Churchill Livingstone, 1999; 16582.
39 Dray A, Perkins M. Bradykinin and inflammatory pain. Trends Neurosci 1993; 16: 994[ISI][Medline]
40 Farquhar-Smith WP, Egertova E, Bradbury EJ, McMahon SB, Rice ASC, Elphick MR. Cannabinoid CB1 receptor expression in rat spinal cord. Mol Cell Neurosci 2000; 15: 51021[ISI][Medline]
41 Field MJ, Bramwell S, Hughes J, Singh L. Detection of static and dynamic components of mechanical allodynia in rat models of neuropathic pain: are they signalled by distinct primary sensory neurones? Pain 1999; 83: 30311[ISI][Medline]
42 Fleetwood-Walker SM, Quinn JP, Wallace C, et al. Behavioural changes in the rat following infection with varicella-zoster virus. J Genet Virol 1999; 80: 24336
43 Flor H, Elbert T, Knecht S, et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 1995; 375: 4824[ISI][Medline]
44 Flor H, Elbert T, Muhlnickel W, Pantev C, Wienbruch C, Taub E. Cortical reorganization and phantom phenomena in congenital and traumatic upper-extremity amputees. Exp Brain Res 1998; 119: 20512[ISI][Medline]
45 Fox A, Eastwood C, Gentry C, Manning D, Urban L. Critical evaluation of the streptozotocin model of painful diabetic neuropathy in the rat. Pain 1999; 81: 30716[ISI][Medline]
46 Gee NS, Brown JP, Dissanayake VUK, Offord J, Thurlow R, Woodruff GN. The novel anticonvulsant drug, Gabapentin (Neurontin), binds to the alpha2-delta subunit of a calcium channel. J Biol Chem 1996; 271: 576876
47 Goff JR, Burkey AR, Goff DJ, Jasmin L. Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour. Neuroscience 1998; 82: 55974[ISI][Medline]
48 Gold MS. Spinal nerve ligation: What to blame for the pain and why. Pain 2000; 84: 11720[ISI][Medline]
49 Gracely RH, Lynch SA, Bennett GJ. Painful neuropathy: altered central processing maintained dynamically by peripheral input. Pain 1992; 51: 17594[ISI][Medline]
50 Guieu R, Peragut JC, Roussel P, et al. Adenosine and neuropathic pain. Pain 1996; 68: 2714[ISI][Medline]
51 Hao JX, Blakeman KH, Yu W, Hultenby K, Xu XJ, Wiesenfeld-Hallin Z. Development of a mouse model of neuropathic pain following photochemically induced ischemia in the sciatic nerve. Exp Neurol 2000; 163: 2318[ISI][Medline]
52 Herzberg U, Eliav E, Bennett GJ, Kopin IJ. The analgesic effects of R(+)-Win 55212'2 mesylate, a high affinity cannabinoid agonist, in a rat model of neuropathic pain. Neurosci Lett 1997; 221: 15760[ISI][Medline]
53 Hohmann AG, Briley EM, Herkenham M. Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Brain Res 1999; 822: 1725[ISI][Medline]
54 Hohmann AG , Herkenham M. Regulation of cannabinoid and mu opioid receptors in rat lumbar spinal cord following neonatal capsaicin treatment. Neurosci Lett 1998; 25: 2136
55 Holdcroft A, Hargreaves KM, Rice AS, et al. Cannabinoids and pain modulation in animals and humans. In: Devor M, Rowbotham RC, Wiesenfeld-Hallin Z, eds. Progress in Pain Research and Management. 2000; 91526
56 Hua XY, Chen P, Yaksh TL. Inhibition of spinal protein kinase C reduces nerve injury-induced tactile allodynia in neuropathic rats. Neurosci Lett 1999; 276: 99102[ISI][Medline]
57 Hwang JH, Yaksh TL. The effect of spinal GABA receptor agonists on tactile allodynia in a surgically-induced neuropathic pain model in the rat. Pain 1997; 70: 1522[ISI][Medline]
58 Idanpaan-Heikkila JJ, Guilbaud G. Pharmacological studies on a rat model of trigeminal neuropathic pain: baclofen, but not carbamazepine, morphine or tricyclic antidepressants, attenuates the allodynia-like behaviour. Pain 1999; 79: 28190[ISI][Medline]
59 Isaacson LG, Saffran BN, Crutcher KA. Nerve growth factor-induced sprouting of mature, uninjured sympathetic axons. J Comp Neurol 1992; 326: 32736[ISI][Medline]
60 Jaggar SI, Habib S, Rice AS. The modulatory effects of bradykinin B1 and B2 receptor antagonists upon viscero-visceral hyper-reflexia in a rat model of visceral hyperalgesia. Pain 1998; 75: 16976[ISI][Medline]
61 Janig W, Levine JD, Michaelis M. Interactions of sympathetic and primary afferent neurons following nerve injury and tissue trauma. Prog Brain Res 1996; 113: 16184[ISI]
62 Jones MG, Munson JB, Thompson SW. A role for nerve growth factor in sympathetic sprouting in rat dorsal root ganglia. Pain 1999; 79: 219[ISI][Medline]
63 Kauppila T. Correlation between autotomy-behavior and current theories of neuropathic pain. Neurosci Biobehav Rev 1998; 23: 11129[ISI][Medline]
64 Kawamata M, Omote K. Involvement of increased excitatory amino acids and intracellular Ca2+ concentration in the spinal dorsal horn in an animal model of neuropathic pain. Pain 1996; 68: 8596[ISI][Medline]
65 Kim KJ, Yoon YW, Chung JM. Comparison of three rodent neuropathic pain models. Exp Brain Res 1997; 113: 2006[ISI][Medline]
66 Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50: 35563[ISI][Medline]
67 Kim YI, Kim SH, Oh EJ, et al. Some membrane property changes following axotomy in A delta-type DRG cells are related to cold allodynia in rat. Neuroreport 1999; 10: 14939[ISI][Medline]
68 Kingery WS, Vallin JA. The development of chronic mechanical hyperalgesia, autotomy and collateral sprouting following sciatic nerve section in rat. Pain 1989; 38: 32132[ISI][Medline]
69 Koerber HR, Mirnics K, Brown PB, Mendell LM. Central sprouting and functional plasticity of regenerated primary afferents. J Neurosci 1994; 14: 365571[Abstract]
70 Kohama I, Ishikawa K, Kocsis JD. Synaptic reorganization in the substantia gelatinosa after peripheral nerve neuroma formation: aberrant innervation of lamina II neurons by Aß afferents. J Neurosci 2000; 20: 153849
71 Kovelowski CJ, Ossipov MH, Sun H, Lai J, Malan TP jr, Porreca F. Supraspinal cholecystokinin may drive tonic descending facilitation mechanisms to maintain neuropathic pain in the rat. Pain 2000; 87: 26573[ISI][Medline]
72 Kral MG, Xiong Z, Study RE. Alteration of Na+ currents in dorsal root ganglion neurons from rats with a painful neuropathy. Pain 1999; 81: 1524[ISI][Medline]
73 Kupers R, Yu W, Persson JK, Xu X, Wiesenfeld-Hallin Z. Photochemically-induced ischemia of the rat sciatic nerve produces a dose-dependent and highly reproducible mechanical, heat and cold allodynia, and signs of spontaneous pain. Pain 1998; 76: 4559[ISI][Medline]
74 Laird JM, Bennett GJ. An electrophysiological study of dorsal horn neurons in the spinal cord of rats with an experimental peripheral neuropathy. J Neurophysiol 1993; 69: 207285
75 Lee BH, Won R, Baik EJ, Lee SH, Moon CH. An animal model of neuropathic pain employing injury to the sciatic nerve branches. Neuroreport 2000; 11: 65761[ISI][Medline]
76 Lee BH, Yoon YW, Chung K, Chung JM. Comparison of sympathetic sprouting in sensory ganglia in three animal models of neuropathic pain. Exp Brain Res 1998; 120: 4328[ISI][Medline]
77 Lekan HA, Carlton SM, Coggeshall RE. Sprouting of A beta fibers into lamina II of the rat dorsal horn in peripheral neuropathy. Neurosci Lett 1996; 208: 14750[ISI][Medline]
78 Levine JD, Taiwao Y. Inflammatory pain. In: Wall PD, Melzack R, eds. Textbook of Pain, 3rd edn. Edinburgh: Churchill Livingstone, 1994; 4556
79 Li J, Simone DA, Larson AA. Windup leads to characteristics of central sensitization. Pain 1999; 79: 7582[ISI][Medline]
80 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 fibres. Pain 2000; 85: 493502[ISI][Medline]
81 Liu CN, Amir R, Devor M. Effect of age and nerve injury on cross-excitation among sensory neurons in rat dorsal root ganglia. Neurosci Lett 1999; 259: 958[ISI][Medline]
82 Liu CN, Michaelis M, Amir R, Devor M. Spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons: Relation to neuropathic pain. J Neurophysiol 2000; 84: 20515
83 Liu X, Eschenfelder S, Blenk KH, Janig W, Habler H. Spontaneous activity of axotomized afferent neurons after L5 spinal nerve injury in rats. Pain 2000; 84: 30918[ISI][Medline]
84 Lyu YS, Park SK, Chung K, Chung JM. Low dose of tetrodotoxin reduces neuropathic pain behaviours in an animal model. Brain Res 2000; 871: 98103[ISI][Medline]
85 Malcangio M, Tomlinson DR. A pharmacologic analysis of mechanical hyperalgesia in streptozotocin/diabetic rats. Pain 1998; 76: 1517[ISI][Medline]
86 Malmberg AB, Basbaum AI. Partial sciatic nerve injury in the mouse as a model of neuropathic pain: behavioral and neuroanatomical correlates. Pain 1998; 76: 21522[ISI][Medline]
87 Mannion RJ, Doubell TP, Coggeshall RE, Woolf CJ. Collateral sprouting of uninjured primary afferent A-fibres into the superficial dorsal horn of the adult rat spinal cord after topical capsaicin treatment to the sciatic nerve. J Neurosci 1996; 16: 518995
88 Mao J, Price DD, Mayer DJ, Lu J, Hayes RL. Intrathecal MK-801 and local nerve anesthesia synergistically reduce nociceptive behaviors in rats with experimental peripheral mononeuropathy. Brain Res 1992; 576: 25462[ISI][Medline]
89 Martini R. Animal models for inherited peripheral neuropathies: chances to find treatment strategies? J Neurosci Res 2000; 61: 24450[ISI][Medline]
90 Matzner O, Devor M. Hyperexcitability at sites of nerve injury depends on voltage-sensitive Na+ channels. J Neurophysiol 1994; 72: 34959
91 McLachlan EM, Janig W, Devor M, Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993; 363: 5436[ISI][Medline]
92 McQuay HJ, Tramer M, Nye BA, Carroll D, Wiffen PJ, Moore RA. A systematic review of antidepressants in neuropathic pain. Pain 1996; 68: 21727[ISI][Medline]
93 Mendell LM. Physiological properties of unmyelinated fiber projection to the spinal cord. Exp Neurol 1966; 16: 31632[ISI][Medline]
94 Merskey H, Bogduk N. Classification of Chronic Pain, 2nd edn. Seattle: IASP Press, 1994; 394
95 Mogil JS. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc Natl Acad Sci USA 1999; 96: 774451
96 Mogil JS, Grisel JE. Transgenic studies of pain. Pain 1998; 77: 10728[ISI][Medline]
97 Mogil JS, Wilson SG, Bon K, et al. Heritability of nociception II. Types of nociception revealed by genetic correlation analysis. Pain 1999; 80: 8393[ISI][Medline]
98 Neil A, Attal N, Guilbaud G. Effects of guanethidine on sensitization to natural stimuli and self-mutilating behaviour in rats with a peripheral neuropathy. Brain Res 1991; 565: 23746[ISI][Medline]
99 Nordin M, Nystrom B, Wallin U, Hagbarth KE. Ectopic sensory discharges and paresthesiae in patients with disorders of peripheral nerves, dorsal roots and dorsal columns. Pain 1984; 20: 23145[ISI][Medline]
100 OmanaZapata I, Khabbaz MA, Hunter JC, Clarke DE, Bley KR. Tetrodotoxin inhibits neuropathic ectopic activity in neuromas, dorsal root ganglia and dorsal horn neurons. Pain 1997; 72: 4149[ISI][Medline]
101 Pan HL, Eisenach JC, Chen SR. Gabapentin suppresses ectopic nerve discharges and reverses allodynia in neuropathic rats. J Pharmacol Exp Ther 1999; 288: 102630
102 Perl ER, Willis WD, eds. Alterations in responsiveness of cutaneous nociceptors: sensitization by noxious stimuli and the induction of adrenergic responsiveness by nerve injury. Hyperalgesia and Allodynia. New York: Raven Press, 1992; 5979
103 Pertwee RG. Pharmacology of cannabinoid CB1 and CB2 receptors. Pharmacol Ther 1997; 74: 12980[ISI][Medline]
104 Petersen M, Eckert AS, Segond von Banchet G, Heppelmann B, Klusch A, Kniffki KD. Plasticity in the expression of bradykinin binding sites in sensory neurons after mechanical nerve injury. Neuroscience 1998; 83: 94959[ISI][Medline]
105 Porreca F, Tang QB, Bian D, Riedl M, Elde R, Lai J. Spinal opioid mu receptor expression in lumbar spinal cord of rats following nerve injury. Brain Res 1998; 795: 197203[ISI][Medline]
106 Quartaroli M, Carignani C, Dal Forno G, et al. Potent antihyperalgesic activity without tolerance produced by glycine site antagonist of N-methyl-D-aspartate receptor GV196771A. J Pharmacol Exp Ther 1999; 290: 15869
107 Rabben T, Skjelbred P, Oye I. Prolonged analgesic effect of ketamine, an N-methyl-D-aspartate receptor inhibitor, in patients with chronic pain. J Pharmacol Exp Ther 1999; 289: 10606
108 Ramer MS, Bisby MA. Rapid sprouting of sympathetic axons in dorsal root ganglia of rats with a chronic constriction injury. Pain 1997; 70: 23744[ISI][Medline]
109 Ramer MS, Thompson SW, McMahon SB. Causes and consequences of sympathetic basket formation in dorsal root ganglia. Pain 1999; 6 (Suppl.): S11120
110 Rice ASC, Casale R. Microneurography and the investigation of pain mechanisms. Pain Rev 1994; 1: 12137
111 Ro L, Chen S, Tang L, Chang H. Local application of anti-NGF blocks the collateral sprouting in rats following chronic constriction injury of the sciatic nerve. Neurosci Lett 1996; 218: 8790[ISI][Medline]
112 Rowbotham MC. Kalso E, McQuay HJ, Wiesenfeld-Hallin Z, eds. The debate over opioids and neuropathic pain. Opioid Sensitivity of Chronic Non-cancer Pain. Seattle: IASP Press, 1999; 18: 30717
113 Rowbotham MC, Harden N, Stacey B, Bernstein P, Magnus-Miller L. Gabapentin for treatment of postherpetic neuralgia. JAMA 1998; 280: 183743
114 Santicioli P, Del Bianco E, Tramontana M, Maggi CA. Adenosine inhibits action potential-dependent release of calcitonin gene-related peptide- and substance P-like immunoreactivities from primary afferents in rat spinal cord. Neurosci Lett 1992; 144: 2114[ISI][Medline]
115 Sebert ME, Shooter EM. Expression of mRNA for neurotrophic factors and their receptors in the rat dorsal root ganglion and sciatic nerve following nerve injury. J Neurosci Res 1993; 36: 35767[ISI][Medline]
116 Seltzer Z, Dubner R, and Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990; 43: 20518[ISI][Medline]
117 Sheen K, Chung JM. Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res 1993; 610: 628[ISI][Medline]
118 Shir Y, Seltzer Z. Effects of sympathectomy in a model of causalgiform pain produced by partial sciatic nerve injury in rats. Pain 1991; 45: 30920[ISI][Medline]
119 Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999; 83: 389400[ISI][Medline]
120 Sivilotti L, Woolf CJ. The contribution of GABAA and glycine receptors to central sensitization: disinhibition and touch-evoked allodynia in the spinal cord. J Neurophysiol 1994; 72: 16979
121 Smith GD, Harrison SM, Birch PJ, Elliott PJ, Malcangio M, Bowery NG. Increased sensitivity to the antinociceptive activity of (+/)-baclofen in an animal model of chronic neuropathic, but not chronic inflammatory hyperalgesia. Neuropharmacology 1994; 33: 11038[ISI][Medline]
122 Sollevi A, Belfrage M, Lundeberg T, Segerdahl M, Hansson P. Systemic adenosine infusion: a new treatment modality to alleviate neuropathic pain. Pain 1995; 61: 1558[ISI][Medline]
123 Sotgiu ML, Biella G. Differential effects of MK-801, a N-methyl-D-aspartate non-competitive antagonist, on the dorsal horn neuron hyperactivity and hyperexcitability in neuropathic rats. Neurosci Lett 2000; 283: 1536[ISI][Medline]
124 Stanfa LC, Dickenson AH, Xu X, Wiesenfeld-Hallin Z. Cholecystokinin and morphine analgesia: variations on a theme. Trend Pharmacol Sci 1994; 15: 656[ISI][Medline]
125 Stein C, Schafer M, Cabot PJ, et al. Peripheral opioid analgesia. Pain Rev 1997; 4: 17387[ISI]
126 Stiller CO, Cui JG, OConnor WT, Brodin E, Meyerson BA, Linderoth B. Release of gamma-aminobutyric acid in the dorsal horn and suppression of tactile allodynia by spinal cord stimulation in mononeuropathic rats. Neurosurgery 1996; 39: 36774[ISI][Medline]
127 Suzuki R, Chapman V, Dickenson AH. The effectiveness of spinal and systemic morphine on rat dorsal horn neuronal responses in the spinal nerve ligation model of neuropathic pain. Pain 1999; 80: 21528[ISI][Medline]
128 Takasaki I, Andoh T, Shiraki K, Kuraishi Y. Allodynia and hyperalgesia induced by herpes simplex virus type-1 infection in mice. Pain 2000; 86: 95101[ISI][Medline]
129 Tandrup T, Woolf CJ, Coggeshall RE. Delayed loss of small dorsal root ganglion cells after transection of the rat sciatic nerve. J Comp Neurol 2000; 422: 17280[ISI][Medline]
130 Taylor CP, Gee NS, Su TZ, Kocsis JD, Welty DF, Brown JP, Dooley DJ, Boden P, Singh L. A summary of mechanistic hypotheses of gabapentin pharmacology. Epilepsy Res 1998; 29: 23349[ISI][Medline]
131 Thompson SW, Bennett DL, Kerr BJ, Bradbury EJ, McMahon SB. Brain-derived neurotrophic factor is an endogenous modulator of nociceptive responses in the spinal cord. Proc Natl Acad Sci USA 1999; 96: 77148
132 Thompson SW, Majithia AA. Leukemia inhibitory factor induces sympathetic sprouting in intact dorsal root ganglia in the adult rat in vivo. J Physiol 1998; 506: 80916
133 Tong YG, Wang HF, Ju G, Grant G, Hokfelt T, Zhang X. Increased uptake and transport of cholera toxin B-subunit in dorsal root ganglion neurons after peripheral axotomy: possible implications for sensory sprouting. J Comp Neurol 1999; 404: 14358[ISI][Medline]
134 Utzschneider D, Kocsis J, Devor M. Mutual excitation among dorsal root ganglion neurons in the rat. Neurosci Lett 1992; 146: 536[ISI][Medline]
135 Wagner R, Janjigian M, Myers RR. Anti-inflammatory interleukin-10 therapy in CCI neuropathy decreases thermal hyperalgesia, macrophage recruitment, and endoneurial TNF-alpha expression. Pain 1998; 74: 3542[ISI][Medline]
136 Wall PD. Neuropathic pain and injured nerve: central mechanisms. Br Med Bull 1991; 47: 63143[Abstract]
137 Wall PD, Devor M. Sensory afferent impulses originate from dorsal root ganglia as well as from the periphery in normal and nerve ligated rats. Pain 1983; 17: 32139[ISI][Medline]
138 Wall PD, Devor M, Inbal FR, et al. Autotomy following peripheral nerve lesions: experimental anaesthesia dolorosa. Pain 1979; 7: 10311[ISI][Medline]
139 Wall PD, Gutnick M. Ongoing activity in peripheral nerves: The physiology and pharmacology of impulses originating from a neuroma. Exp Neurol 1974; 43: 58093
140 Wall PD, Woolf CJ. The brief and the prolonged facilitatory effects of unmyelinated afferent input on the rat spinal cord are independently influenced by peripheral nerve section. Neuroscience 1986; 17: 11991205[ISI][Medline]
141 Waxman SG, Dib Hajj S, Cummins TR, Black JA. Sodium channels and pain. Proc Natl Acad Sci USA 1999; 96: 76359
142 Waxman SG, Kocsis JD, Black JA. Type III sodium channel mRNA is expressed in embryonic but not adult spinal sensory neurons, and is reexpressed following axotomy. J Neurophysiol 1994; 72: 46670
143 White DM, Cousins MJ. Effect of subcutaneous administration of calcium channel blockers on nerve injury-induced hyperalgesia. Brain Res 1998; 801: 508[ISI][Medline]
144 Woolf CJ. Windup and central sensitization are not equivalent. Pain 1996; 66: 1058[ISI][Medline]
145 Woolf CJ and Mannion RJ. Pain: neuropathic pain: aetiology, symptoms, mechanisms and managment. Lancet 1999; 353: 195964[ISI][Medline]
146 Woolf CJ, Shortland P, Coggeshall RE. Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature 1992; 355: 758[ISI][Medline]
147 Woolf CJ, Shortland P, Reynolds M, Ridings J, Doubell T, Coggeshall RE. Reorganization of central terminals of myelinated primary afferents in the rat dorsal horn following peripheral axotomy. J Comp Neurol 1995; 360: 12134[ISI][Medline]
148 Wu CL, Marsh A, Dworkin RH. The role of sympathetic nerve blocks in herpes zoster and postherpetic neuralgia. Pain 2000; 87: 1219[ISI][Medline]
149 Xiao WH, Bennett GJ. Synthetic omega-conopeptides applied to the site of nerve injury suppress neuropathic pains in rats. J Pharmacol Exp Ther 1995; 274: 66672[Abstract]
150 Xu X, Hao J, Aldskogius H, Seiger A, Wiesenfeld-Hallin Z. Chronic pain-related syndrome in rats after ischemic spinal cord lesion: a possible animal model for pain in patients with spinal cord injury. Pain 1992; 48: 27990[ISI][Medline]
151 Xu X, Puke MJ, Verge VM, Wiesenfeld-Hallin Z, Hughes J, Hokfelt T. Up-regulation of cholecystokinin in primary sensory neurons is associated with morphine insensitivity in experimental neuropathic pain in the rat. Neurosci Lett 1993; 152: 12932[ISI][Medline]
152 Yaksh TL. Behavioral and autonomic correlates of the tactile evoked allodynia produced by spinal glycine inhibition: effects of modulatory receptor systems and excitatory amino acid antagonists. Pain 1989; 37: 11123[ISI][Medline]
153 Yiangou Y, Birch R, Sangameswaran L, Eglen R, Anand P. SNS/PN3 and SNS2/NaN sodium channel-like immunoreactivity in human adult and neonate injured sensory nerves. FEBS Lett 2000; 467: 24952[ISI][Medline]
154 Yoon YW, Na HS, Chung JM. Contributions of injured and intact afferents to neuropathic pain in an experimental rat model. Pain 1996; 64: 2736[ISI][Medline]
155 Zhang X, Bao L, Shi TJ, Ju G, Elde R, Hokfelt T. Down-regulation of mu-opioid receptors in rat and monkey dorsal root ganglion neurons and spinal cord after peripheral axotomy. Neuroscience 1998; 82: 22340[ISI][Medline]