Annals of Neurosciences, Vol 14, No 4 (2007)
Annals of Neurosciences, Volume 14, Issue 4 (October), 2007
RECENT DEVELOPMENTS IN THE STUDY OF SPINAL CORD INJURY AND NEUROPATHIC PAIN
Corresponding Author :
Daniel K Resnick
Department of Neurological Surgery
University of Wisconsin School of Medicine and Public Health
K4/834 Clinical Science Center
600 Highland Ave Madison, WI53792
Phone: (608) 263–9651 Fax: (608) 263–1728
Email: resnick@neurosurg.wise.edu
(Recieved on 10.07.2007)
Abstract
Spinal cord injury (SCI) represents a profound clinical problem for which there exists limited effective therapy. The clinical management of SCI is frequently complicated by the subsequent development of chronic neuropathic pain syndromes. The pathogenesis of central neuropathic pain following SCI is unclear, although evidence exists for the involvement of a diverse range of factors. Key mediators of neuropathic pain include the inflammatory process, excitatory neurotransmitters, opioid and cannabinoid receptors, and ion channel activity. Recent studies conducted in animal models have yielded promising results for the development of neuropathic pain therapies that target these mediators, but clinical results have been disappointing. In this review, we provide an overview of current animal models of SCI and neuropathic pain, discuss recent advances in the study of the aforementioned neuropathic pain mediators, and review the current clinical treatment of neuropathic pain with emphasis on areas that show promise for future investigation.
Key Words: Spinal Cord Injuries; Pain; Nociceptors; Inflammation; Model Animal.
Introduction
Spinal cord injury (SCI) may result in devastating motor and sensory deficits for which current therapy is largely ineffective. Additionally, SCI can induce the development of chronic neuropathic pain (NP) states that may be even more debilitating than any functional deficit. The development of some degree of central NP is believed to occur in the majority of SCI patients and may cause significant discomfort and disability in many areas of a patient's life [1]. Although progress in the development of effective clinical therapies for SCI and NP has been slow, many recent advances have been made that provide insight into the cellular and molecular mechanisms of SCI that give hope for future success in the treatment of SCI and associated pain syndromes. Presently, we review the current experimental models of SCI and NP as well as significant recent developments in the study of the pathology and treatment of SCI and chronic NP.
Spinal Cord Injury Animal Models
Several laboratory models to address the development of NP following SCI have been designed. Among these are spinal hemisection, spinal ischemic injury, quisqualte-induced excitotoxic lesions, clip-compression lesions, and argon laser induced lesions [2–8]. Although these models have been validated for laboratory testing, they lack clinical relevance. Siddall et al. have used a relatively crude model of SCI (Allen weight drop) and a relatively subjective measure of pain (vocalization after von Frey fiber stimulation) to analyze NP at a single, acute time point [9]. Hulsebosch et al. described a contusion SCI model utilizing the Multicenter Animal Spinal Cord Injury Study (MASCIS) Impactor, which involved the analysis of thermal and mechanical allodynia 28 days after a 12.5 g/cm injury [10]. In this model, allodynia was observed in a region extending 1–2 levels caudal to the lesion and 5–6 levels rostrally. The authors demonstrated an ameliorating effect on thermal withdrawl latency and von Frey testing with the analgesic gabapentin. Interestingly, Siddall et al. have reported that approximately 50% of their injured animals developed NP, with the incidence of NP behavior higher by approximately two-thirds in animals undergoing a relatively mild injury compared to those animals undergoing a more severe injury [9,11]. The study of Hulsebosch et al., however, described development of allodynia in all animals subjected to moderate SCI. There is thus some disagreement in the literature regarding the incidence of allodynia following contusion injury in the spinal cord of rats. Furthermore, it has been demonstrated that perioperative analgesics can alter the incidence, severity, and timing of NP [12,13]. Exploration of the genetic alterations and protein changes determining the development and maintenance of chronic NP is dependent on a reproducible, clinically relevant animal model of SCI; further analgesic intervention as a means to decrease the incidence of disabling NP is clearly necessary.
Peripheral Nerve Injury Animal Models Ischemic
Although peripheral injury models are not directly applicable to SCI, they have proven useful in the study of NP. The ischemic (photochemical) model simulates an ischemic injury by producing a blood clot in the sciatic nerve. Photochemical interactions are produced in the sciatic nerve by injecting erythrosine B intravenously while irradiating the exposed nerve. The interactions produce a blood clot that elicits the ischemic effects [14]. This type of injury is advantageous in that there is minimal surgery involved and the injury can be controlled by managing the duration of irradiation. Several neuropathic symptoms result, such as thermal hyperalgesia (TH), cold allodynia and spontaneous pain-lifting and shaking of the paw [15]. This model is also used in the spinal cord; spinal ischemic injuries occur in the grey and/or white matter depending on the severity. The neuropathic outcomes include short-lived hypersensitivity and alloydnia [1].
Spinal Nerve Ligation
Ligations are often used for peripheral nerve injuries (PNI) and are typically of three main types: spinal nerve ligation, partial sciatic ligation and spared nerve injury. Spinal nerve ligation (SNL) injury involves ligation of one or more nerves leading to the foot. The nerve or group of nerves is then severed. This results in spontaneous pain development as demonstrated by oral wetting of the inflamed area and extensive nail growth [16]. This behavior is similar to behavior seen in humans with NP that wet the inflamed area with water and overgrow their nails to avoid the pain caused by trimming [17]. Alloydnia and chronic hyperalgesia also result. Although SNL involves more extensive surgery than the other ligation techniques, this model has several advantages over the others: the injuries are less varied and the levels of intact and injured nerves are completely separate. This allows for possible future studies to be done on the nerves.
Partial Sciatic Ligation
The partial sciatic ligation (PSL) model involves ligation of a small area of the sciatic nerve. The results of this model include spontaneous pain development, hypersensitivity to harmful and innocuous stimuli and hyperalgesia to repetitive touch (something not observed in chronic constriction injury model) and heat. As in many other models, these symptoms can be alleviated with sympathectomy, similar to humans [18].
Spared Nerve Injury
The spared nerve injury (SNI) involves axotomy of the tibial and common peroneal nerve branches of the sciatic nerve. This results in a strong reaction to harmless mechanical and mild non-noxious cold stimuli. Immediate (less than 24hours) chronic hyperalgesia, both thermal and mechanical, develops near the injured area [19]. These symptoms highly correlate with those found in human patients with NP [20].
Chronic Constriction Injury
Another area of PNI models is partial nerve injuries, namely chronic constriction injury (CCI). CCI involves placing loose ligatures around the sciatic nerve in order to elicit nerve swelling and constriction. The resulting symptoms are spontaneous lifting of the foot, oral wetting of the inflamed area and a guarded stance. Overgrown claws and autotomy were also observed. This model is used for observation of neuropathic pain development and gene expression in the dorsal horn following injury. Loose ligation has been especially useful in understanding the development and time-course of neuropathic pain. In this model, thermal hyperalgesia (TH), one of the behavioral signs of neuropathic pain, is reversible. This allows for studies of dorsal horn sensory processing during neuropathic pain manifestation and following neuropathic pain resolution. Our lab has previously reported long-lasting synaptic plasticity coinciding with TH manifestation, and a loss of the long-lasting plasticity upon disappearance of TH [21]. More recently, a direct association between cyclic AMP response element binding protein (CREB) activation and TH has been described [23]. Loose ligation along with the other peripheral nerve injury models described are important tools in examining treatments of spinal and supraspinal nerve allodynia and hyperalgesia following a partial nerve injury.
Inflammatory Response in SCI
The inflammatory process is a complex host defense mechanism that is of particular significance in the pathogenesis of SCI as well as in the development of ensuing pain syndromes. Inflammation is a highly regulated process that involves a progressive cascade of activity. Prominent components of the acute inflammatory response include changes at the vascular and biochemical level, including the accumulation of cytokines, chemokines, prostaglandins, and other inflammatory factors, complement activation, and leukocyte migration to the injury site. Although the inflammatory response is largely consistent across most tissues of the body, several important distinctions must be taken into account when considering the inflammatory response within the central nervous system (CNS) [24,25].
In particular, the CNS contains several highly specialized cell types (i.e. central neurons, astrocytes, oligodendrocytes, microglial cells) which are not present in systemic tissues. Anatomical considerations are also important. The lack of a lymphatic drainage system and the inability to significantly expand (i.e. dura, skull, spinal canal, etc) expose the CNS to substantial risk from increased tissue pressure, ischemia, and damage secondary to inflammation. Furthermore, the limited regenerative capacity of central neural tissue magnifies the outcome of any damage caused by the inflammatory process. Finally, the presence of the blood-brain barrier significantly delays peripheral leukocyte migration into central neural tissue [26]. A recent study, however, demonstrated that a spinal nerve lesion in the rat can induce defects of the blood-spinal cord barrier, leading to astrocyte activation [27]. In this study, maximal blood-spinal cord permeability was observed two weeks following injury, with persistent elevation of permeability still evident at ten weeks. Therefore, it may be possible that local increase in permeability of the blood-spinal cord barrier is an important mediator of inflammation following spinal nerve injury and an important contributor to the development of NP.
The fundamental purpose of the inflammatory response is to eliminate offending pathogens, remove necrotic tissue, and mediate the repair of damaged tissue. It is apparent that inflammation in the CNS has several beneficial outcomes, particularly in the reparative process following injury. Activated leukocytes phagocytose necrotic cells and the cytotoxic factors released by damaged cells, which serves to limit the extent of tissue damage induced by the initial injury. Additionally, several studies have demonstrated an upregulation of neurotrophic factors by both microglial cells and astrocytes in response to inflammatory signals in mice, rats, and humans [28–30], while another study has identified a neuroprotective effect of pro-inflammatory cytokines in a rat model of SCI [31]. Other studies have indicated that the neurotrophic factors induced by inflammation may also play a central role in the development of chronic pain syndromes [22,32]. Recent studies have highlighted potential roles for both neurotrophin growth factor and brain-derived neurotrophic factor in the pathogenesis of NP via the modulation of pain afferent excitability and nociceptor sensitization [33–36].
Although beneficial effects of inflammation following SCI have been well described, the inflammatory response is also capable of causing substantial damage to central nervous tissue and is increasingly recognized as a key element of the pathogenesis of NP. In some cases, the secondary damage due to acute inflammation may be more significant than the primary insult to the spinal cord. Following traumatic SCI, the final lesion size is found to be significantly larger than the lesion size immediately following injury [37]. The cascade of events leading to secondary damage is believed to involve many inflammatory mediators, including nitric oxide (NO), bradykinins, prostaglandins, and tumor necrosis factor alpha (TNF-a) [38].
The Role of Inflammatory Mediators in the Pathogenesis of Pain Syndromes
Nitric Oxide
Nitric oxide (NO) is a potent inflammatory mediator that is believed to be an important factor in the development of secondary tissue damage following SCI. In the inflammatory response, NO induces vasodilation and mediates other cellular activities through induction of cyclic guanosine monophosphate (cGMP) in addition to participating in the production of free radicals via reaction with superoxide to generate the cytotoxic peroxynitrite anion. Due to the short in vivo half-life of NO, tissue levels of NO are highly dependent on NO synthase (NOS) activity. There exist three primary isoforms of NO synthase: endothelial, neuronal, and inducible. Endothelial and neuronal NO synthase are constitutively expressed at low levels in their respective tissues and are modulated by intracellular Ca2+ levels, while inducible NO synthase (iNOS) is induced by cytokine activation during the inflammatory process. A number of inflammatory cytokines are known to induce iNOS, including TNF-a and interleukin-1-β, which act via the nuclear transcription factor NF-?B.
As iNOS induction requires several hours following injury, it has been suggested that constitutively expressed NOS isoforms are most important in NO-mediated secondary tissue damage in the acute phase of SCI [39]. The regulation of constitutive NOS activity in the acute phase is complex and appears to have both beneficial and detrimental effects on recovery. A recent study has indicated that the induction of beneficial versus detrimental NO activity may be age dependent, with more neuroprotective NO activity observed in young rats and more neurodestructive NO activity observed in adult rats following SCI [40]. The effect of constitutive NOS isoform activity on NP has not been extensively studied, but it has been suggested that neuronal NOS activity may be a mediator of chronic allodynia [41].
Although iNOS does not appear to be a significant factor in the acute response to SCI, iNOS may be an important factor in ongoing inflammatory neuropathy subsequent to the acute phase and recent research has identified iNOS as an important contributor to the development of NR Persistent upregulation of iNOS for 14 days following contusive SCI in a rat model has been reported [42], and inhibition of iNOS activity has provided important information on the functional effects of NO in SCI models. The acute administration of selective iNOS inhibitors have been shown to improve both functional and histopathological outcome in models of traumatic SCI [43,44] and to alleviate NP in a chronic constrictive model [45]. Agmatine, an inhibitor of all NO synthase isoforms and the N-methyl-D-aspartate glutamate receptor, has been shown to reduce inflammation-induced hyperalgesia and allodynia following excitotoxic SCI [46]. Interestingly, agmatine has also recently been shown to be released from spinal synaptosomes in response to spinal nerve depolarization in an in vitro study, suggesting a possible role for endogenous agmatine in the modulation of inflammation [47]. Endogenous agmatine, however, has not been studied in vivo and it remains unclear whether the effect of endogenous agmatine is functionally comparable to exogenously administered agmatine. Inhibition of iNOS expression has also yielded intriguing results. A study of knockout mice lacking the iNOS gene found improved functional outcome at 14 days following compressive SCI [48]. NF-?B inhibition has also been demonstrated mediate a reduction in inflammation and oxidative stress following traumatic SCI in rats, a result that was correlated with reduced iNOS expression [49], although pain behaviors were not assessed in either of these studies.
Despite substantial data indicating a primarily detrimental role for NO following SCI, there is also evidence to suggest that some aspects of NO activity may also have a beneficial role in recovery via a variety of neuroprotective mechanisms. A recent comparison of the efficacy of gabapentin, a drug currently used in clinical NP management, with a novel NO-releasing gabapentin derivative demonstrated superior reduction in pain behavior in rats treated with the NO-releasing derivative following injury to both the spinal cord and the sciatic nerve, although the mechanism remains unclear [50]. It is evident that the role of NO following SCI is highly complex, and both the beneficial and detrimental actions of NO must be taken into account when considering the development of novel NOS-based therapeutic strategies for SCI and NP.
Prostaglandins
Prostaglandins are another important mediator of inflammatory pathology. Prostaglandins are produced from arachidonic acid through the cyclooxygenase (COX) pathway. There are two isoforms of COX enzymes, the constitutive COX-1 enzyme and the inducible COX-2 enzyme. It is believed that constitutive COX expression is primarily responsible for the mediation of homeostatic prostaglandin function, while inducible COX expression is primarily involved in inflammatory responses, although these roles are not exclusive [51]. Following SCI in rats, COX-2 mRNA expression has been shown to be upregulated within 2 hours of injury with increased mRNA production observed for at least 48 hours, while selective inhibition of COX-2 activity has been shown to improve functional outcome following spinal cord injury [52]. There is also currently an interest in the role of COX-2 induction in the onset of NP following SCI, particularly as it relates to the production of prostaglandin E2 (PGE2), a factor which has been implicated in central hyperalgesia secondary to inflammation [53–55]. It has been proposed that a primary mechanism for the development PGE2-mediated hyperalgesia following SCI involves the PGE2-dependent activation of a microglia-neuron signaling pathway [56]. Several studies have investigated the effect of COX-2 inhibitors on prostaglandin production and hyperalgesia, noting significant reductions in PGE2 production with more modest attenuation of pain behaviors in rats [57–59].
Bradykinin
The kinin system represents another important element of the inflammatory response. The kinin system is responsible for the genesis of bradykinin (BK), a vasoactive peptide with known hyperalgesic effects [60]. BK interacts with the G protein-coupled BK B1 receptor to induce Ca2+ influx into sensory neurons [61]. The B1 receptor has also been shown mediate pain sensitivity in animal models through interaction with the capsaicin-sensitive vanilloid receptor 1 (TRPV-1) [62,63]. Accordingly, the B1 and TRPV-1 receptors have been targets in the investigation of NP. Recent work in our laboratory has found that in a rat model of contusive SCI, animals that subsequently developed hyperalgesic behavior exhibited significant upregulation of both B1 and TRPV-1 receptor expression both at the injury epicenter and rostral to the injury site when compared with animals that did not develop hyperalgesic behavior [64]. We have also shown that B1 and TRPV-1 antagonists have antihyperalgesic effects following SCI in rats, indicating a possible role for both receptors in the development of central NP following SCI [65]. Studies performed in other laboratories have supported this finding. Increased sensitization of spinal TRPV-1 receptors has been found to be a mediator of mechanical allodynia in a rat chronic constriction injury model, while B1 receptor knock-out mice have been shown to develop less NP than wild-type mice following peripheral nerve lesion [66,67]. Recently, BK was also proposed to have a potential neuroprotective role, modulating the inflammatory response by attenuating cytokine release from activated microglia in cell culture, though the functional significance of this result has not been investigated in an animal model [68].
TNF-α
TNF-α is major pro-inflammatory cytokine that has been identified as key mediator of inflammatory damage and NP following SCI. TNF-α is initially synthesized as a type II transmembrane protein that is proteolytically cleaved to yield the soluble TNF-α product, with both the membrane-bound and the soluble product exhibiting biological activity. In a study of traumatic SCI in mice, TNF-α mRNA expression was found to be induced as early as 15 minutes following injury, while a separate study found elevated brain TNF-α protein expression within 6 hours following SCI, indicating a potential role for TNF-α in the induction of NP at both the spinal and supraspinal levels [69,70]. TNF-α interacts with a diverse family of TNF receptors, most of which are expressed by immune cells, making TNF-α an important intermediate in the innate immune response during inflammation. TNF receptors have also been localized to dorsal root afferents throughout the spinal cord [71]. TNF receptor activation can induce a variety of effects, including cell proliferation, differentiation, and apoptosis [72].
Similar to many other inflammatory mediators, the precise role of TNF-α following SCI is controversial, with evidence to suggest both positive and negative impact on secondary damage processes and the development of NP [24]. Proposed neuroprotective roles include protection against excitotoxic amino acids and maintenance of Ca2+ homeostasis, though the neuroprotective efficacy of TNF-α may be both concentration and age dependent [73,74]. Despite these beneficial effects, there is increasing evidence linking TNF-α activity with neurodestruction and pain development. TNF-α has been proposed to play a central role in both neuronal and glial apoptosis following SCI, possibly via a NO-mediated mechanism [75]. Multiple studies have reported increased mechanical allodynia in transgenic mice with astrocytic expression of TNF-α [76,77]. Increased brainstem TNF-α activity has also been reported in rats experiencing persistent pain in a chronic constriction model, strengthening the notion that TNF-α may be involved in the development of central NP [78]. Further studies on TNF-α activity and pain behavior in SCI models is needed to further evaluate the nature of TNF-α modulation of NP development.
Other Inflammatory Factors
Several other inflammatory factors are of interest in the pathogenesis and treatment of SCI and NP. Investigation of the anti-inflammatory and corresponding neuroprotective effects of peroxisome proliferator-activated receptor-? (PPAR?) agonists has been promising. Earlier studies of PPARγ agonists have demonstrated neuroprotective effects in a rat model of cerebral ischemia, while a more recent study in our laboratory has found beneficial effects of the acute administration of thiazolidinedione class PPARγ agonists on histopathological, functional, and pain outcomes in a rat model of contusive SCI [79–81]. There has also been considerable interest in the role of T-lymphocytes in the pathology of SCI. T-lymphocytes have classically been viewed as mediators of neuropathology in inflammatory injury. Although neuroprotective effects of myelin basic protein-reactive T-cells in contusive SCI have been reported, more recent data has challenged these results, finding both increased histological damage as well as impaired functional recovery in rats immunized with myelin basic protein [82,83]. Athymic rats have also been shown to have improved functional recovery following SCI [84]. Injections of pro-inflammatory cytokine-secreting type 1 T-lymphocytes have been reported to induce hyperalgesia following peripheral constrictive nerve injury, while anti-inflammatory type 2 T-lymphocytes mediated a mild antihyperalgesic effect [85]. Unfortunately, little data on the effects of T-cell infiltration on pain behavior following SCI have been reported.
Anti-inflammatory Treatment Following SCI
Although it appears that SCI and the onset of NP are intimately related to inflammatory pathology, the efficacy of antiinflammatory treatment following SCI has been disappointing. The only anti-inflammatory medication currently in regular clinical use for acute SCI is the glucocorticosteroid methylprednisolone. Clinical evidence supporting the use of methylprednisolone (MTH) was first presented in the National Acute Spinal Cord Injury Study (NASCIS) trials [86–88]. Although none of the subsequent NASCIS trials found statistically significant differences in primary neurologic outcome analysis, post hoc analysis indicated mild improvement in motor and sensory function with high-dose MTH treatment if administered within 8 hours of injury. Despite the questionable validity of the post hoc analysis of the NASCIS data, high dose MTH subsequently gained widespread use in the treatment of SCI. However, the use of steroids in the medical management of SCI remains controversial; the risk of adverse side effects, including sepsis, pulmonary embolism, and myopathy, may outweigh the marginal clinical benefit provided by high dose MTH treatment [89,90].
In addition to glucocorticoid therapy, there is also clinical potential for the use of more specific antagonists of the inflammatory cascade. As noted above, specific modulation of the many inflammatory mediators, including NO, prostaglandins, the kinin system, and TNF-a elicited promising improvements in both functional recovery and pain behavior in a variety of experimental models. It is possible that more specific inhibition of certain inflammatory processes may ultimately prove more efficacious than the broad-spectrum anti-inflammatory effect of glucocorticoid treatment. However, it must be noted that the results observed in experimental models of SCI may not be applicable to the true clinical situation, and there is currently no strong clinical data supporting the use of other anti-inflammatory treatments for SCI.
Development and Maintenance of Chronic NP
The etiology of chronic NP includes not only the inflammatory processes described above but also several non-inflammatory mechanisms of central and peripheral hypersensitization [91]. The chronic state of NP as described thus far is dependent upon structural changes in primary afferent nerve terminals, loss of inhibitory inputs on dorsal horn cells, astrocytic activation, glutamatergic excitation and excitotoxicity, cytokine modulation, and altered gene expression. This section will discuss the effects of agonists and antagonists on systems known to be involved in the development and maintenance of chronic NP.
NMDA Receptor Antagonists
The excitatory glutamatergic system has long been implicated in NP due to its role in excitatory synaptic plasticity and excitotoxicity [92]. Three receptors are described that induce excitation and neuronal plasticity in response to glutamate: NMDA receptors, AMPA receptors, and kainite receptors. Because of the relatively small contribution of AMPA and kainite receptors to nociception, the majority of the interest in the study of NP has been directed towards the NMDA receptor class. This unique ionotropic receptor is permeable to monovalent ions and calcium, is blocked by extracellular magnesium, and requires simultaneous depolarization and agonist binding for opening. Glycine is a coagonist with glutamate for efficient activation of this channel. The NMDA receptor was associated with nociception over 20 years ago when NMDA receptor antagonists were first shown to reduce nociceptive hyperexcitability and potentiation in rat dorsal hom cells [93,94].
Recently, the direct role of this system in central sensitization leading to hyperalgesia and allodynia has been more completely described [95]. Direct protein kinase A-mediated phosphorylation of NMDA channels in pain-related central synaptic plasticity in rat neurons has been shown [96], although other studies have suggested that NMDA receptors are not involved in peripheral synaptic plasticity [97]. Also, NMDA knockdown has been shown to have no effect on heat, cold or mechanical withdrawal latencies, but prevention of chronic pain behavior following intraplantar formalin injection was observed [98]. NMDA receptors have thus been recognized as possible pharmacological targets in chronic, but not acute, NP.
Several studies have shown promise in the specific targeting of NMDA receptors to reduce pain related behavior in animal models. Following contusive SCI, gacyclidine, a non-competitive NMDA receptor antagonist, led to recovery of motor function, decreased cystic cavitation, and reduced astrogliosis [99]. It has also been shown that blockade of either the NMDA receptor (with the competitive antagonist AP-5) or the AMPA and kainite receptors (with competitive non-NMDA antagonist NBQX) reduces mechanical, but not thermal, allodynia [100]. These studies illustrate the action of NMDA receptors in secondary but not acute NP. Further, Yoshimura et al. has demonstrated that administration of MK-801 (a non-specific NMDA channel antagonist) and AP-5 (which is specific to the receptor subtype found in dorsal horn cells) both produced dose-dependent reductions in thermal hyperalgesia, but neither had an analgesic effect following a CCI [101]. Antihyperalgesic and analgesic effects of the NMDA antagonist neramexane have also been recently described [102]. A promising new study using the novel noncompetitive NMDA antagonist and monoamine oxidase-A inhibitor CHF3381 showed reduced secondary hyperalgesia in the heat-capsaicin model of human pain [103]. However, NMDA antagonist administration in humans has been unsuccessful in reducing NP. Randomized placebo-controlled trials of dextromethorphan, memantine, and GV196771, three NMDA antagonists, all showed no significant pain reduction [104]. Human administration of NMDA antagonists is hindered by the widespread presence of NMDA receptors throughout the CNS. Non-specific blockade of NMDA receptors can quickly lead to psychotropic effect, limiting therapeutic dosing capabilities in the treatment of NP. Recently, the antagonist CNS 5161 has been shown to be reasonably well tolerated up to a potential therapeutic dose, though randomized control trials have not yet been performed [105]. Encouragingly, down-regulation of central sensitization and antiallodynia appears to follow short-acting NMDA antagonism in animal models [106]. These recent findings suggest that short term NMDA antagonist therapy may be effective in long-term treatment of chronic NP. Further research into therapeutic effectiveness of NMDA antagonists in humans is necessary.
Opioid Receptor Agonists
Opioid agonists have long been used to produce antinociception. However, it has been demonstrated that morphine and other common opioid agonists do not show a significant analgesic effect in chronic NP [107]. One possible mechanism may be reduced opioid sensitivity from the loss of presynaptic opioid receptors on damaged central processes of peripheral nociceptive cells [108]. Another important consideration is the distribution of opioid receptors throughout the nervous system. Three receptor subtypes, d, ?, and μ, have been characterized. Changes in expression of the μ and d receptors have been observed following nervous system lesions, and localization to the dorsal horn of the spinal cord has been noted. The μ subtype is the most noteworthy opioid receptor in NP. In a recent study, overexpression of μ receptors was noted following a chronic constriction injury [109]. Decreased pre- and post-synaptic μ receptor activity following PNI has also been observed [110]. The d receptor has been found to play an important role in NP as well. Administration of deltorphin II, a d receptor agonist, reversed cold hyperalgesia and attenuated mechanical allodynia [111]. Together these findings indicate direct involvement of the opioid system, notably the μ and d receptors, in NP. However, due to both the diminished opioid sensitivity in NP and the addictive potential in therapeutic opiate administration, no clearly effective human treatments involving the opioid receptors have emerged to date.
In animal models, several studies of opiod agonists have demonstrated antiallodynia and antihyperaglesia following both PNI and SCI. Administration of the μ receptor agonists codeine, morphine, and methadone, resulted in attenuation of pain following chronic constriction injury and spinal cord injury in a rat model via both morphine and methadone, with methadone showing the greatest efficacy; codeine, however, showed minimal effect on pain [112]. Methadone, along with its agonistic effect on μ receptors, has also been shown to antagonize the NMDA receptor, which may explain the increased efficacy observed [113]. Nonetheless, the observed antinociceptive differences between codeine, morphine, and methadone were directly proportional to the different binding affinities for cloned human μ opioid receptors [114]. Recently, more effective antinociception has been found in rat models of formalin-induced pain with peripherally acting opioid agonists, such as naloxone methiodide and 6 amino acid derivatives of 14-O-methyloxymorphone [115]. This finding suggests that long-term pain may be effectively targeted with opioid agonists with limited access to the CNS, attenuating the addictive properties of opiate therapeutic treatment. In clinical trials, oxycodone, morphine, and methadone have not shown significant relief in chronic NP [104]. Tramadol has demonstrated a significant yet widely variable analgesic effect, showing potential as a therapeutic agent in humans, although further investigation is necessary to determine efficacy.
GABA Receptor Agonists
The importance of the GABAergic system in spinal nociceptive processing has been long appreciated, with much evidence suggesting that injury-induced derangement of normal GABA function leads to the development of NP. GABA receptors are found on pre- and post-synaptic sites of primary afferent terminals, as well as in 24–33% of interneurons in laminae I-IV in the spinal cord dorsal horn [116]. GABA receptors are ligand-mediated chloride channels, and there are two classified subtypes: GABAA and GABAB. Both GABAA and GABAB agonists have been shown to attenuate chronic NP and decrease hyperexcitability [117].
Recently, further studies have supported a loss of GABA inhibition in the development of chronic NP. Subarachnoid implantation of GABA-producing human neuronal hNT2.17 cells in rats can attenuate allodynia and hyperalgesia following excitotoxic injury [118]. It has also been demonstrated that loss of the GABAergic system may not necessary for the development of TH [119]. However, following a CCI via loose ligation of the sciatic nerve in a rat model, Miletic et al. found not only prevention of long-lasting potentiation with the administration of the GABAA receptor agonist muscimol, but also a significant decrease in the GABA receptor transporter GAT-1 in dorsal horn cells [120]. Current research is investigating the dependence of the GABAergic system on intracellular chloride concentrations in NP associated with contusion SCI.
In the maintenance of intracellular chloride concentration, the Na+/K+/C1- cotransporter 1 (NKCC1, CI- influx) has become a point of interest. Deficits in thermal nociceptive thresholds and an absent GABAA receptor-mediated anion outward flux in NKCC1-/-knockout mice have been demonstrated [121]. Nesic et al. have shown a 5-fold increase in NKCC1 rostral to SCI in rats and a 6-fold increase caudal to the lesion [122]. It has also been shown that the NKCC1 inhibitor bumetanide inhibits itch and flare responses to histamine in human skin and attenuates phase I and II behavioral responses in the formalin model of tissue injury-induced pain [123]. A further indication of cation-chloride cotransporter involvement in hyperalgesia has been demonstrated by a single study reporting decreased K+/C1-cotransporter 2 (KCC2, CI- efflux) expression resulting from a partial nerve injury induced by sciatic cuff [124]. However, the full significance of GABAergic disinhibition in NP remains unclear.
Cannabinoid Receptor Agonists
Cannabinoids (CB) have been shown to modulate NP [125]. Their mechanism of their action is poorly understood, but it has been shown that they activate both G-protein coupled receptors, such as CB1 and CB2 receptors, as well as ionotropic receptors, like TRPV1 [126–128]. Overexpression of both CB1 and CB2 receptors has been observed following injury [129]. Also, spinal administration of CB has been shown to decrease hyperalgesia in multiple chronic pain models [130,131]. The effect of CB on nociception in the CNS appears to be mediated primarily by the CB1 receptor, however, a recent study using CB1 knockout mice demonstrated no apparent role of CB1 receptors in adaptive responses following PNI, indicating a role primarily in the process of central sensitization following SCI [132]. Intracellular CB1 receptors have been observed in the spinal cord, the dorsal root ganglia, and the peripheral terminals of C fibers [133]. These CB1 receptors are co-localized with the TRPV1 receptor, an extracellular receptor with a documented role in the transmission of pain in TH [64,65]. TRPV1 receptors appear to be partly responsible for the pain during TH, whereas CB1 receptors are thought to counteract TH by inhibiting TRPVl-mediated nociception.
Hermann et al. have shown that pre-treatment of human kidney cells with CB1 receptor agonists leads to inhibition of TRPV1 activity or to its enhanced stimulation, depending on whether or not the cAMP-signaling pathway is concurrently activated [133]. Although the interaction between CB1 and TRPV1 does not appear to be direct, CB1-coupled intracellular signaling events might be necessary to observe the enhancement of TRPV1-induced biological effects, and endogenous substances that are capable of activating both receptor types might produce different overall biological effects depending on which of the two receptors they activate first. Anandamide, which acts as a full agonist to TRPV1 receptors and can indirectly activate CB1 receptors, was found to reverse TH in a nonspecific manner [134]. WIN 55,212–2, a CB1 and CB2 receptor agonist, was also recently shown to specifically reduce TH in a chronic pain state [135].
More research is necessary to determine the role and potential for pharmacological targeting of the CB system in NP. An important question raised by current research is the relative contribution of G-protein coupled receptors versus ionotropic mechanisms in mediating TH and NP. One study has even suggested that CB inhibition of TRPV1 is CB1 and CB2 independent [136]. Future studies should focus on understanding the signaling processes mediating the desensitization of TRPV1 by CB, as it could have profound mechanistic and therapeutic value.
Adrenergic Agonists
The a2 adrenergic receptor has also been implicated in chronic NP. Analgesic effects noted following intrathecal administration of the a2 receptor agonist Clonidine strongly support the involvement of the adrenergic system in modulation of nociception. a2 receptors have been localized to the dorsal horn of the spinal cord and Clonidine is thought to attenuate nociception at both pre- and post-synaptic sites in the dorsal horn via either direct inhibition of synaptic transmission or inhibition of substance P [137,138]. Clonidine has become a common clinical tool in chronic pain management, despite minimal literature supporting its efficacy; Ackermann et al. demonstrated little relief after monotherapy with Clonidine in human subjects experiencing chronic NP, though combined therapy with opioids intrathecally provided relief greater than 2 years in duration for 20% of the observed subjects [139]. The use of Clonidine and other adrenergic agonists in NP management is currently in need of more investigation, as overall success rate is low despite a noteworthy efficacy in a limited group of patients.
Ion Channels
Recently, interest in the role of ion channel activity in NP has developed, focusing particularly on the voltage-gated calcium channel CaV and the voltage-gated sodium channel NaV1.3. The proposed relationship between CaV channels and NP involves the presynaptic release of glutamate, acting as an excitatory amino acid in the dorsal horn and resulting in hyperalgesia [140]. Tetrodotoxin (TTX)-resistant voltage-gated sodium channels have also been shown to accumulate near the terminals of peripheral nociceptive neurons in the dorsal horn following injury [141]. Further, Lampert et al. observed specific upregulation of the NaV1.3 channel, demonstrating the TTX-resistant activity noted in the dorsal horn previously [142]. However, a recent study indicated that the NaV1.8 channel blocker ambroxol attenuates chronic, neuropathic, and inflammatory pain in animal models [143]. Randomized clinical trials with the sodium channel blocker lidocaine have shown promise, though it has been suggested that channel blockers more specific to the channel subtypes related to NP are necessary for effective therapeutic treatment [144].
Gene Expression
Several recent studies reported global changes in gene expression following PNI or SCI [145–147]. It has been documented that TH is accompanied by activity-dependent long-lasting synaptic plasticity in the superficial spinal dorsal horn, and that the disappearance of the TH coincided with a loss of the long-lasting synaptic plasticity [21]. More recently it has been reported that there was a similar association between the TH and activation of cAMP response element binding protein (CREB), and that this activation was also reversible because it lasted only as long as the TH [23]. Changes in the expression of genes and gene products involved in inflammation, excitotoxicity, and cell cycle functions have been documented in the early stages following SCI [148,149]. However, a strain-dependent effect on gene expression following SCI has been demonstrated in rats, emphasizing the importance of testing novel therapies focused on gene expression on a variety of animal species prior to testing on humans [150]. These studies suggest a significant, reversible, species-specific shift in the manner in which spinal neurons process sensory information.
Clinical Treatment of NP
NP is notable for its resistance to conventional analgesic medications, and the persistent nature of most NP syndromes requires careful consideration of the long-term side effects of any candidate medication for the treatment of NP. Accordingly, progress in the development of NP therapies has been slow. Medications that have thus far proven most useful in NP management and have been targets of recent research include antiepileptics/anticonvulsants and tricyclic antidepressants. Opioids, which were discussed previously, have also been used in chronic pain management, though their proper role is controversial [151].
Antiepileptic drugs have long been recognized as having clinical efficacy in the treatment of NP, although the precise mechanism by which they act remains unclear. It is believed that antiepileptics primarily reduce hypersensitization of pain afferents by modulating Ca2+ channel and Na+ channel activities, although certain antiepileptics may have additional modes of action [152]. The antiepileptic gabapentin in particular has been a primary target of recent research on NP following SCI. Multiple studies have shown gabapentin to be effective in the clinical treatment of SCI [153–155]. It has been proposed that gabapentin reduces neuronal excitability through the regulation of voltage-dependent Ca2+ channel activity as well as through inhibition of the release of the excitatory neurotransmitter glutamate within the spinal cord [140,156]. Other antiepileptics that have recently shown promise include lamotrigine, pregabalin, and lacosamide. Lamotrigine is thought to reduce pain sensitivity by inhibiting Na+ channel activity, while pregabalin is thought to work via Ca2+ channel inhibition in a manner similar to gabapentin [157,158]. Both of these drugs have been shown to be useful in the clinical setting [160,161]. The new antiepileptic lacosamide has also shown an antihyperalgesic effect in an animal model of SCI, though its mechanism of action is not well understood and its clinical efficacy remains unevaluated [162].
Antidepressants have also been useful in chronic pain management. The mode of action is not well understood, but appears to be primarily modulated by a serotonin-mediated mechanism. Studies in animal models have demonstrated that 5-HT1A receptor agonists may preempt NP development as well as relieve existing pain following SCI [163,164]. Although serotonin alone may mediate antihyperalgesic effects, concurrent inhibition of the reuptake of other monoamines may also potentiate the effects of selective serotonin reuptake inhibitors [165]. Interestingly, endogenous serotonin has also been found to promote the development of NP in an animal model though an undetermined mechanism [166]. It is clear that the role of monoamines in mediating NP development is complex and further research is needed for mechanistic clarification.
Conclusion
Although spinal cord injuries result in devastating motor and sensory deficits, the development of chronic NP states may be even more debilitating than any functional deficit. The cellular and molecular mechanisms in the development of pain behaviors are poorly understood, but many recent advances have been made that provide insight into SCI. We have reviewed current experimental models of NP following injury and associated significant recent developments in the study of the pathology and treatment of SCI and chronic NP.
References:
1. Yezierski RR Spinal cord injury: a model of central neuropathic pain. Neurosignals 2005; 14:182–93.
2. Christensen MD, Everhart AW, Pickelman JT, Hulsebosch CE. Mechanical and thermal allodynia in chronic central pain following spinal cord injury. Pain 1996; 68:97–107.
3. Gwak YS, Nam TS, Paik KS, et al. Attenuation of mechanical hyperalgesia following spinal cord injury, by administration of antibodies to nerve growth factor in the rat. Neurosci Lett 2003; 336:117–20.
4. Xu XJ, Hao JX, Aldskogius H, et al. 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; 48:279–90.
5. Yezierski RP, Liu S, Ruenes GL, et al. Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain 1998; 75:141–55.
6. Bruce JC, Oatway MA, Weaver LC. Chronic pain after clip-compression injury of the rat spinal cord. Exp Neurol 2002; 178:33–48.
7. Xu XJ, Alster R Wu WP, Hao JX, Wiesenfeld-Hallin Z. Increased level of cholecystokinin in cerebrospinal fluid is associated with chronic painlike behavior in spinally injured rats. Peptides 2001; 22:1305–8.
8. Gwak YS, Hains BC, Johnson KM, Hulsebosch CE. Effect of age at time of spinal cord injury on behavioral outcomes in rat. J Neurotrauma 2004; 21:983–93.
9. Siddall PJ, Xu CL, Floyd N, Keay KA. C-fos expression in the spinal cord of rats exhibiting allodynia following contusive spinal cord injury. Brain Res 1999; 851:281–6.
10. Hulsebosch CE, Xu GY, Perez-Polo JR, et al. Rodent model of chronic central pain after spinal cord contusion injury and effects of gabapentin. J Neurotrauma 2000; 17:1205–17.
11. Siddall P, Xu CL, Cousins M. Allodynia following traumatic spinal cord injury in the rat. NeUroreport 1995; 6:1241–4.
12. Stewart LS, Martin WJ. Influence of postoperative analgesics on the development of neuropathic pain in rats. Comp Med 2003; 53:29–36.
13. Kouya PF, Hao JX, Xu XJ. Buprenorphine alleviates neuropathic painlike behaviors in rats after spinal cord and peripheral nerve injury. Eur J Pharmacol 2002; 450:49–53.
14. Watson BD; Prado R, Dietrich WD, et al. Photochemically induced spinal cord injury in the rat. Brain Res 1986; 367:296–300.
15. Kupers R, Yu W, Persson JK, Xu XJ, 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; 76:45–59.
16. Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain 1992; 50:355–63.
17. Tahmoush AJ. Causalgia: redefinition as a clinical pain syndrome. Pain 1981; 10:187–97.
18. Seltzer Z, Dubner R, Shir Y. A novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990; 43:205–18.
19. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 2000; 87:149–58.
20. Woolf CJ, Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353:1959–64.
21. Draganic P Miletic G, Miletic V. Changes in post-tetanic potentiation of A-fiber dorsal horn field potentials parallel the development and disappearance of neuropathic pain after sciatic nerve ligation in rats. Neurosci Lett 2001 ; 301:127–30.
22. Miletic G, Miletic V. Increases in the concentration of brain derived neurotrophic factor in the lumbar spinal dorsal horn are associated with pain behavior following chronic constriction injury in rats. Neurosci Lett 2002; 319:137–40.
23. Miletic G, Pankratz MT, Miletic V. Increases in the phosphorylation of cyclic AMP response element binding protein (CREB) and decreases in the content of calcineurin accompany thermal hyperalgesia following chronic constriction injury in rats. Pain 2002; 99:493–500.
24. Bethea JR, Dietrich WD. Targeting the host inflammatory response in traumatic spinal cord injury. Curr Opin Neurol 2002; 15:355–60.
25. Lucas SM, Rothwell NJ, Gibson RM. The role of inflammation in CNS injury and disease. Br J Pharmacol 2006; 147:232–40.
26. Ransohoff RM, Kivisakk P, Kidd G. Three or more routes for leukocyte migration into the central nervous system. Nat Rev Immunol 2003; 3:569–81.
27. Gordh T, Chu H, Sharma HS. Spinal nerve lesion alters blood-spinal cord barrier function and activates astrocytes in the rat. Pain 2006; 124:211–21.
28. Ho A, Blum M. Regulation of astroglial-derived dopaminergic neurotrophic factors by interleukin-1 beta in the striatum of young and middle-aged mice. Exp Neurol 1997; 148:348–59.
29. Goss JR, O'Malley ME, Zou L, et al. Astrocytes are the major source of nerve growth factor upregulation following traumatic brain injury in the rat. Exp Neurol 1998; 149:301–9.
30. Heese K, Hock C, Otten U. Inflammatory signals induce neurotrophin expression in human microglial ceils. J Neurochem 1998; 70:699–707.
31. Klusman I, Schwab ME. Effects of pro-inflammatory cytokines in experimental spinal cord injury. Brain Res 1997; 762:173–84.
32. Pezet S, McMahon SB. Neurotrophins: mediators and modulators of pain. Annu Rev Neurosci 2006; 29:507–38.
33. Coull JA, Beggs S, Boudreau D, et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 2005; 438:1017–21.
34. Matayoshi S, Jiang N, Katafuchi T, et al. Actions of brain-derived neurotrophic factor on spinal nociceptive transmission during inflammation in the rat. J Physiol 2005; 569:685–95.
35. Guo W, Robbins MT, Wei F, et al. Supraspinal brain-derived neurotrophic factor signaling: a novel mechanism for descending pain facilitation. J Neurosci 2006; 26:126–37.
36. Hathway GJ, Fitzgerald M. Time course and dose-dependence of nerve growth factor-induced secondary hyperalgesia in the mouse. J Pain 2006; 7:57–61.
37. Liu XZ, Xu XM, Hu R, et al. Neuronal and glial apoptosis after traumatic spinal cord injury. J Neurosci 1997; 17:5395–406.
38. Hausmann ON. Post-traumatic inflammation following spinal cord injury. Spinal Cord 2003; 41:369–78.
39. Conti A, Miscusi M, Cardali S, et al. Nitric oxide in the injured spinal cord: synthases cross-talk, oxidative stress and inflammation. Brain Res Rev 2007; 54:205–18.
40. Yang JY, Kim HS, Lee JK. Changes in nitric oxide synthase expression in young and adult rats after spinal cord injury. Spinal Cord 2007; [in press].
41. Hao JX, Xu XJ. Treatment of a chronic allodynia-like response in spinally injured rats: effects of systemically administered nitric oxide synthase inhibitors. Pain 1996; 66:313–9.
42. Xu J, Kim GM, Chen S, et al. iNOS and nitrotyrosine expression after spinal cord injury. J Neurotrauma 2001; 18:523–32.
43. Chatzipanteli K, Garcia R, Marcillo AE, et al. Temporal and segmental distribution of constitutive and inducible nitric oxide synthases after traumatic spinal cord injury: effect of aminoguanidine treatment. J Neurotrauma 2002; 19:639–51.
44. Yu Y, Matsuyama Y, Nakashima S, et al. Effects of MPSS and a potent iNOS inhibitor on traumatic spinal cord injury. Neuroreport 2004; 15:2103–7.
45. Naik AK, Tandan SK, Kumar D, Dudhgaonkar SP. Nitric oxide and its modulators in chronic constriction injury-induced neuropathic pain in rats. Eur J Pharmacol 2006; 530:59–69.
46. Fairbanks CA, Schreiber KL, Brewer KL, et al. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Nati Acad Sci USA 2000; 97:10584–9.
47. Goracke-Postle CJ, Nguyen HO, Stone LS, Fairbanks CA. Release of tritiated agmatine from spinal synaptosomes. Neuroreport 2006; 17:13–7.
48. Isaksson J, Farooque M, Olsson Y Improved functional outcome after spinal cord injury in iNOS-deficient mice. Spinal Cord 2005; 43:167–70.
49. La Rosa G, Cardali S, Genovese T, et al. Inhibition of the nuclear factor-kappaB activation with pyrrolidine dithiocarbamate attenuating inflammation and oxidative stress after experimental spinal cord trauma in rats. J Neurosurg Spine 2004; 1:311–21.
50. Wu WP Hao JX, Ongini E, et al. A nitric oxide (NO)-releasing derivative of gabapentin, NCX 8001, alleviates neuropathic pain-like behavior after spinal cord and peripheral nerve injury. Br J Pharmacol 2004; 141:65–74.
51. Bingham S, Beswick PJ, Blum DE, et al. The role of the cylooxygenase pathway in nociception and pain. Semin Cell Dev Biol 2006; 17:544–54.
52. Resnick DK, Graham SH, Dixon CE, Marion DW. Role of cyclooxygenase 2 in acute spinal cord injury. J Neurotrauma 1998; 15:1005–13.
53. Takeda K, Sawamura S, Tamai H, et al. Role for cyclooxygenase 2 in the development and maintenance of neuropathic pain and spinal glial activation. Anesthesiology 2005; 103:837–44.
54. O'Rielly DD, Loomis CW. Spinal prostaglandins facilitate exaggerated A- and C-fiber-mediated reflex responses and are critical to the development of allodynia early after L5-L6 spinal nerve ligation. Anesthesiology 2007; 106:795–805.
55. Bianchi M, Martucci C, Ferrano P, et al. Increased tumor necrosis factor-alpha and prostaglandin E2 concentrations in the cerebrospinal fluid of rats with inflammatory hyperalgesia: the effects of analgesic drugs. Anesth Analg 2007; 104:949–54.
56. Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci 2007; 27:2357–68.
57. Tegeder I, Niederberger E, Vetter G, et al. Effects of selective COX-1 and -2 inhibition on formalin-evoked nociceptive behaviour and prostaglandin E(2) release in the spinal cord. J Neurochem 2001 ; 79:777–86.
58. Hains BC, Yucra JA, Hulsebosch CE. Reduction of pathological and behavioral deficits following spinal cord contusion injury with the selective cyclooxygenase-2 inhibitor NS-398. J Neurotrauma 2001; 18:409–23.
59. Schafers M, Marziniak M, Sorkin LS, et al. Cyclooxygenase inhibition in nerve-injury- and TNF-induced hyperalgesia in the rat. Exp Neurol 2004; 185:160–8.
60. Couture R, Harrisson M, Vianna RM, Cloutier F. Kinin receptors in pain and inflammation. Eur J Pharmacol 2001; 429:161–76.
61. Linhart O, Obreja O, Kress M. The inflammatory mediators serotonin, prostaglandin E2 and bradykinin evoke calcium influx in rat sensory neurons. Neuroscience 2003; 118:69–74.
62. Shin J, Cho H, Hwang SW, et al. Bradykinin-12-lipoxygenase-VR1 signaling pathway for inflammatory hyperalgesia. Proc Natl Acad Sci USA 2002; 99:10150–5.
63. Sugiura T, Tominaga M, Katsuya H, Mizumura K. Bradykinin lowers the threshold temperature for heat activation of vanilloid receptor 1. J Neurophysiol 2002; 88:544–8.
64. DomBourian MG, Turner NA, Gerovac TA, et al. B1 and TRPV-1 receptor genes and their relationship to hyperalgesia following spinal cord injury. Spine 2006; 31:2778–82.
65. Rajpal S, Gerovac TA, Turner NA, et al. Antihyperalgesic effects of vanilloid-1 and bradykinin-1 receptor antagonists following spinal cord injury in rats. J Neurosurg Spine 2007; 6:420–4.
66. Kanai Y, Nakazato E, Fujiuchi A, et al. Involvement of an increased spinal TRPV1 sensitization through its up-regulation in mechanical allodynia of CCI rats. Neuropharmacology 2005; 49:977–84.
67. Ferreira J, Beirith A, Mori MA, et al. Reduced nerve injury-induced neuropathic pain in kinin B1 receptor knock-out mice. J Neurosci 2005; 25:2405–12.
68. Noda M, Kariura Y, Pannaseli U, et al. Neuroprotective role of bradykinin because of the attenuation of pro-inflammatory cytokine release from activated microglia. J Neurochem 2007; 101:397–410.
69. Pineau I, Lacroix S. Proinflammatory cytokine synthesis in the injured mouse spinal cord: multiphasic expression pattern and identification of the cell types involved. J Comp Neurol 2007; 500:267–85.
70. Brewer KL, Nolan TA. Spinal and supraspinal changes in tumor necrosis factor-alpha expression following excitotoxic spinal cord injury. J Mol Neurosci 2007; 31:13–21.
71. Holmes GM, Hebert SL, Rogers RC, Hermann GE. Immunocytochemical localization of TNF type 1 and type 2 receptors in the rat spinal cord. Brain Res 2004; 1025:210–9.
72. Hehlgans T, Pfeffer K. The intriguing biology of the tumour necrosis factor/tumour necrosis factor receptor superfamily: players, rules and the games. Immunology 2005; 115:1–20.
73. Cheng B, Christakos S, Mattson MP. Tumor necrosis factors protect neurons against metabolic-excitotoxic insults and promote maintenance of calcium homeostasis. Neuron 1994; 12:139–53.
74. Viel JJ, McManus DQ, Smith SS, Brewer GJ. Age- and concentration-dependent neuroprotection and toxicity by TNF in cortical neurons from beta-amyloid. J Neurosci Res 2001; 64:454–65.
75. Yune TY, Chang MJ, Kim SJ, et al. Increased production of tumor necrosis factor-alpha induces apoptosis after traumatic spinal cord injury in rats. J Neurotrauma 2003; 20:207–19.
76. DeLeo JA, Rutkowski MD, Stalder AK, Campbell IL. Transgenic expression of TNF by astrocytes increases mechanical allodynia in a mouse neuropathy model. Neuroreport 2000; 11:599–602.
77. Peng XM, Zhou ZG, Glorioso JC, et al. Tumor necrosis factor-alpha contributes to below-level neuropathic pain after spinal cord injury. Ann Neurol 2006; 59:843–51.
78. Covey WC, Ignatowski TA, Renauld AE, et al. Expression of neuron-associated tumor necrosis factor alpha in the brain is increased., during persistent pain. Reg Anesth Pain Med 2002; 27:357–66.
79. Zhao Y, Patzer A, Gohlke P, et al. The intracerebral application of the PPARgamma-ligand pioglitazone confers neuroprotection against focal ischaemia in the rat brain. Eur J Neurosci 2005; 22:278–82.
80. Luo Y, Yin W, Signore AP, et al. Neuroprotection against focal ischemic brain injury by the peroxisome proliferator-activated receptor-gamma agonist rosiglitazone. J Neurochem 2006; 97:435–48.
81. Park SW, Yi JH, Miranpuri G, et al. Thiazolidinedione class of peroxisome proliferator-activated receptor gamma agonists prevents neuronal damage, motor dysfunction, myelin loss, neuropathic pain, and inflammation after spinal cord injury in adult rats. J Pharmacol Exp Ther 2007; 320:1002–12.
82. Hauben E, Butovsky O, Nevo U, et al. Passive or active immunization with myelin basic protein promotes recovery from spinal cord contusion. J Neurosci 2000; 20:6421–30.
83. Jones TB, Ankeny DP, Guan Z, et al. Passive or active immunization with myelin basic protein impairs neurological function and exacerbates neuropathology after spinal cord injury in rats. J Neurosci 2004; 24:3752–61.
84. Potas JR, Zheng Y, Moussa C, et al. Augmented locomotor recovery after spinal cord injury in the athymic nude rat. J Neurotrauma 2006; 23:660–73.
85. Moalem G, Xu K, Yu L. T lymphocytes play a role in neuropathic pain following peripheral nerve injury in rats. Neuroscience 2004; 129:767–77.
86. Bracken MB, Collins WF, Freeman DF, et al. Efficacy of methylprednisolone in acute spinal cord injury. JAMA 1984; 251:45–52.
87. Bracken MB, Shepard MJ, Collins WF; et al. A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. Results of the Second National Acute Spinal Cord Injury Study. N Engl J Med 1990; 322:1405–11.
88. Bracken MB, Shepard MJ, Holford TR, et al. Administration of methylprednisolone for 24 or 48 hours or tirilazad mesylate for 48 hours in the treatment of acute spinal cord injury. Results of the Third National Acute Spinal Cord Injury Randomized Controlled Trial. National Acute Spinal Cord Injury Study. JAMA 1997; 277:1597–604.
89. Hurlbert RJ. Strategies of medical intervention in the management of acute spinal cord injury. Spine 2006; 31:16–21.
90. Hadley MN, Walters BC, Grabb PA, et al. Guidelines for the management of acute cervical spine and spinal cord injuries. Clin Neurosurg 2002; 49:407–98.
91. Finnerup NB, Jensen TS. Mechanisms of disease: mechanism-based classification of neuropathic pain-a critical analysis. Nat Clin Pract Neurol 2006; 2:107–15.
92. Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-D-aspartate (NMDA) receptors in pain: a review. Anesth Analg 2003; 97:1108–16.
93. Davies J, Miller AJ, Sheardown MJ. Amino acid receptor mediated excitatory synaptic transmission in the cat red nucleus. J Physiol 1986; 376:13–29.
94. Dickenson AH, Sullivan AF. Evidence for a role of the NMDA receptor in the frequency dependent potentiation of deep rat dorsal horn nociceptive neurones following C fibre stimulation. Neuropharmacology 1987; 26:1235–8.
95. Huang C, Li HT, Shi YS, et al. Ketamine potentiates the effect of electroacupuncture on mechanical allodynia in a rat model of neuropathic pain. Neurosci Lett 2004; 368:327–31.
96. Bird GC, Lash LL, Han JS, et al. Protein kinase A-dependent enhanced NMDA receptor function in pain-related synaptic plasticity in rat amygdala neurones. J Physiol 2005; 564:907–21.
97. Aley KO, Levine JD. Different peripheral mechanisms mediate enhanced nociception in metabolic/toxic and traumatic painful peripheral neuropathies in the rat. Neuroscience 2002; 111:389–97.
98. Bleakman D, Alt A, Nisenbaum ES. Glutamate receptors and pain. Semin Cell Dev Biol 2006; 17:592–604.
99. Feldblum S, Arnaud S, Simon M, et al. Efficacy of a new neuroprotective agent, gacyclidine, in a model of rat spinal cord injury. J Neurotrauma 2000; 17:1079–93.
100. Bennett AD, Everhart AW, Hulsebosch CE. Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury. Brain Res 2000; 859:72–82.
101. 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; 56:21–8.
102. Klein T, Magerl W, Hanschmann A, et al. Antihyperalgesic and analgesic properties of the N-methyl-d-aspartate (NMDA) receptor antagonist neramexane in a human surrogate model of neurogenic hyperalgesia. Eur J Pain 2007; [in press].
103. Mathiesen O, Imbimbo BP, Hilsted KL, et al. CHF3381, a N-methyl-D-aspartate receptor antagonist and monoamine oxidase-A inhibitor, attenuates secondary hyperalgesia in a human pain model. J Pain 2006; 7:565–74.
104. Hempenstall K, Nurmikko TJ, Johnson RW, et al. Analgesic therapy in postherpetic neuralgia: a quantitative systematic review. PLOS Med 2005; 2:164.
105. Forst T, Smith T, Schutte K, et al. Dose escalating safety study of CNS 5161 HCl, a new neuronal glutamate receptor antagonist (NMDA) for the treatment of neuropathic pain. Br J Clin Pharmacol 2007.
106. Christoph T, Schiene K, Englberger W, et al. The antiallodynic effect of NMDA antagonists in neuropathic pain outlasts the duration of the in vivo NMDA antagonism. Neuropharmacology 2006; 51:12–7.
107. Amer S, Meyerson BA. Lack of analgesic effect of opioids on neuropathic and idiopathic forms of pain. Pain 1988; 33:11–23.
108. Przewlocki R, Przewlocka B. Opioids in chronic pain. Eur J Pharmacol 2001; 429:79–91.
109. Walczak JS, Pichette V, Leblond F, et al. Characterization of chronic constriction of the saphenous nerve, a model of neuropathic pain in mice showing rapid molecular and electrophysiological changes. J Neurosci Res 2006; 83:1310–22.
110. Kohno T, Ji RR, Ito N, et al. Peripheral axonal injury results in reduced mu opioid receptor pre- and post-synaptic action in the spinal cord. Pain 2005; 117:77–87.
111. Holdridge SV, Cahill CM. Spinal administration of a delta opioid receptor agonist attenuates hyperalgesia and allodynia in a rat model of neuropathic pain. Eur J Pain 2007; 11:685–93.
112. Erichsen HK, Hao JX, Xu XJ, Blackburn-Munro G. Comparative actions of the opioid analgesics morphine, methadone and codeine in rat models of peripheral and central neuropathic pain. Pain 2005; 116:347–58.
113. Ebert B, Andersen S, Krogsgaard-Larsen P. Ketobemidone, methadone and pethidine are non-competitive N-methyl-D-aspartate (NMDA) antagonists in the rat cortex and spinal cord. Neurosci Lett 1995; 187:165–8.
114. Gourlay GK. Advances in opioid pharmacology. Support Care Cancer 2005; 13:153–9.
115. Obara I, Makuch W, Spetea M, et al. Local peripheral antinociceptive effects of 14-O-methyloxymorphone derivatives in inflammatory and neuropathic pain in the rat. Eur J Pharmacol 2007; 558:60–7.
116. Bowery NG, Hudson AL, Price GW. GABAA and GABAB receptor site distribution in the rat central nervous system. Neuroscience 1987; 20:365–83.
117. Gwak YS, Tan HY, Nam TS, et al. Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury. J Neurotrauma 2006; 23:1111–24.
118. Eaton MJ, Wolfe SQ, Martinez M, et al. Subarachnoid transplant of a human neuronal cell line attenuates chronic allodynia and hyperalgesia after excitotoxic spinal cord injury in the rat. J Pain 2007; 8:33–50.
119. Polgar E, Hughes DI, Riddell JS, et al. Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain 2003; 104:229–39.
120. Miletic G, Draganic P, Pankratz MT, Miletic V. Muscimol prevents long-lasting potentiation of dorsal horn field potentials in rats with chronic constriction injury exhibiting decreased levels of the GABA transporter GAT-1. Pain 2003; 105:347–53.
121. Sung KW, Kirby M, McDonald MP, et al. Abnormal GABAA receptor-mediated currents in dorsal root ganglion neurons isolated from Na-K-2Cl cotransporter null mice. J Neurosci 2000; 20:7531–8.
122. Nesic O, Lee J, Johnson KM, et al. Transcriptional profiling of spinal cord injury-induced central neuropathic pain. J Neurochem 2005; 95:998–1014.
123. Price TJ, Cervero F, de Koninck Y. Role of cation-chloride-cotransporters (CCC) in pain and hyperalgesia. Curr Top Med Chem 2005; 5:547–55.
124. Coull JA, Boudreau D, Bachand K, et al. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 2003; 424:938–42.
125. Patwardhan AM, Jeske NA, Price TJ, et al. The cannabinoid WIN 55,212–2 inhibits transient receptor potential vanilloid 1 (TRPV1) and evokes peripheral antihyperalgesia via calcineurin. Proc Natl Acad Sci USA 2006; 103:11393–8.
126. Zygmunt PM, Petersson J, Andersson DA, et al. Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide. Nature 1999; 400:452–7.
127. Watanabe H, Vriens J, Prenen J, et al. Anandamide and arachidonic acid use epoxyeicosatrienoic acids to activate TRPV4 channels. Nature 2003; 424:434–8.
128. Jordt SE, Bautista DM, Chuang HH, et al. Mustard oils and cannabinoids excite sensory nerve fibres through the TRP channel ANKTM1. Nature 2004; 427:260–5.
129. Walczak JS, Pichette V, Leblond F, et al. Characterization of chronic constriction of the saphenous nerve, a model of neuropathic pain in mice showing rapid molecular and electrophysiological changes. J Neurosci Res 2006; 83:1310–22.
130. Croxford JL. Therapeutic potential of cannabinoids in CNS disease. CNS Drugs 2003; 17:179 -202.
131. Rice AS, Farquhar-Smith WP, Nagy I. Endocannabinoids and pain: spinal and peripheral analgesia in inflammation and neuropathy. Prostaglandins Leukot Essent Fatty Acids 2002; 66:243–56.
132. Pol O, Murtra P, Caracuel L, et al. Expression of opioid receptors and cfos in CB1 knockout mice exposed to neuropathic pain. Neuropharmacology 2006; 50:123–32.
133. Hermann H, De Petrocellis L, Bisogno T, et al. Dual effect of cannabinoid CB1 receptor stimulation on a vanilloid VR1 receptor-mediated response. Cell Mol Life Sci 2003; 60:607–16.
134. Rajpal S, Gerovac TA, Turner NA, et al. Selective inhibition of thermal hyperalgesia following spinal cord injury with selective Bl receptor antagonists versus TRPV1 antagonists. J Neurosurg Spine 2007; [in press].
135. Hama A, Sagen J. Antinociceptive effect of cannabinoid agonist WIN 55,212–2 in rats with a spinal cord injury. Exp Neurol 2007; 204:454–7.
136. Sagar DR, Smith PA, Millns PJ, et al. TRPV1 and CB(1) receptor-mediated effects of the endovanilloid/endocannabinoid N-arachidonoyl-dopamine on primary afferent fibre and spinal cord neuronal responses in the rat. Eur J Neurosci 2004; 20:175–84.
137. Osenbach RK, Harvey S. Neuraxial infusion in patients with chronic intractable cancer and noncancer pain. Curr Pain Headache Rep 2001; 5:241–9.
138. Hassenbusch SJ, Garber J, Buchser E, Du Pen S. Alternative intrathecal agents for the treatment of pain. Neuromodulation 1999; 2:85–91.
139. Ackerman LL, Follett KA, Rosenquist RW. Long-term outcomes during treatment of chronic pain with intrathecal Clonidine or clonidine/opioid combinations. J Pain Symptom Manage. 2003; 26:668–77.
140. Coderre TJ, Kumar N, Lefebvre CD, Yu JS. Evidence that gabapentin reduces neuropathic pain by inhibiting the spinal release of glutamate. J Neurochem 2005; 94:1131–9.
141. Waxman SG, Dib-Hajj S, Cummins TR, Black JA. Sodium channels and pain. Proc Natl Acad Sci USA 1999; 96:7635–9.
142. Lampert A, Hains BC, Waxman SG. Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury. Exp Brain Res 2006;174:660–6.
143. Gaida W, Klinder K, Arndt K, Weiser T. Ambroxol, a Navl.8-preferring Na(+) channel blocker, effectively suppresses pain symptoms in animal models of chronic, neuropathic and inflammatory pain. Neuropharmacology 2005; 49:1220–7.
144. Finnerup NB, Biering-Sørensen F, Johannesen IL, et al. Intravenous lidocaine relieves spinal cord injury pain: a randomized controlled trial. Anesthesiology 2005; 102:1023–30.
145. Valder CR, Liu JJ, Song YH, Luo ZD. Coupling gene chip analyses and rat genetic variances in identifying potential target genes that may contribute to neuropathic allodynia development. J Neurochem 2003; 87:560–73.
146. Rabert D, Xiao Y, Yiangou Y, et al. Plasticity of gene expression in injured human dorsal root ganglia revealed by GeneChip oligonucleotide microarrays. J Clin Neurosci 2004; 11:289–99.
147. Resnick DK, Schmitt C, Miranpuri GS, et al. Molecular evidence of repair and plasticity following spinal cord injury. Neuroreport 2004; 15:837–9.
148. Carmel JB, Galante A, Soteropoulos P, et al. Gene expression profiling of acute spinal cord injury reveals spreading inflammatory signals and neuron loss. Physiol Genomics 2001; 7:201–13.
149. Di Giovanni S, Knoblach SM, Brandoli C, et al. Gene profiling in spinal cord injury shows role of cell cycle in neuronal death. Ann Neurol 2003; 53:454–68.
150. Schmitt C, Miranpuri GS, Dhodda VK, et al. Changes in spinal cord injury-induced gene expression in rat are strain-dependent. Spine J 2006; 6:113–9.
151. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J Med 2003; 349:1943–53.
152. Eisenberg E, River Y, Shifrin A, Krivoy N. Antiepileptic drugs in the treatment of neuropathic pain. Drugs 2007; 67:1265–89.
153. To TR Lim TC, Hill ST, et al. Gabapentin for neuropathic pain following spinal cord injury. Spinal Cord 2002; 40:282–5.
154. Ahn SH, Park HW, Lee BS, et al. Gabapentin effect on neuropathic pain compared among patients with spinal cord injury and different durations of symptoms. Spine 2003; 28:341–6.
155. Levendoglu F, Ogun CO, Ozerbil O, et al. Gabapentin is a first line drug for the treatment of neuropathic pain in spinal cord injury. Spine 2004; 29:743–51.
156. Li CY, Zhang XL, Matthews EA, et al. Calcium channel alpha2delta1 subunit mediates spinal hyperexcitability in pain modulation. Pain 2006; 125:20–34.
157. Cheung H, Kamp D, Harris E. An in vitro investigation of the action of lamotrigine on neuronal voltage-activated sodium channels. Epilepsy Res 1992; 13:107–12.
158. Field MJ, Cox PJ, Stott E, et al. Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci USA 2006; 103:17537–42.
160. Finnerup NB, Sindrup SH, Bach FW, et al. Lamotrigine in spinal cord injury pain: a randomized controlled trial. Pain 2002; 96:375–83.
161. Siddali PJ, Cousins MJ, Otte A, et al. Pregabalin in central neuropathic pain associated with spinal cord injury: a placebo-controlled trial. Neurology 2006; 67:1792–800.
162. Hao JX, Stohr T, Selve N, et al. Lacosamide, a new anti-epileptic, alleviates neuropathic pain-like behaviors in rat models of spinal cord or trigeminal nerve injury. Eur J Pharmacol 2006; 553:135–40.
163. Wu WP, Hao JX, Xu XJ, et al. The very-high-efficacy 5-HT1A receptor agonist, F 13640, preempts the development of allodynia-like behaviors in rats with spinal cord injury. Eur J Pharmacol 2003; 478:131–7.
164. Colpaert FC, Wu WP, Hao JX, et al. High-efficacy 5-HT1A receptor activation causes a curative-like action on allodynia in rats with spinal cord injury. Eur J Pharmacol 2004; 497:29–33.
165. Pedersen LH, Nielsen AN, Blackburn-Munro G. Anti-nociception is selectively enhanced by parallel inhibition of multiple subtypes of monoamine transporters in rat models of persistent and neuropathic pain. Psychopharmacology (Berl) 2005; 182:551–61.
166. Rahman W, Suzuki R, Webber M, et al. Depletion of endogenous spinal 5-HT attenuates the behavioural hypersensitivity to mechanical and cooling stimali induced by spinal nerve ligation. Pain 2006; 123:264–74.
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