Central sensitization and pain after spinal cord injury

Seminars in Pain Medicine Vol. 1 No. 3 2003

Central Sensitization and Pain After Spinal Cord Injury CLAIRE E. HULSEBOSCH, PhD

ABSTRACT Spinal cord injuries (SCIs) result in a devastating loss of function below the level of the lesion in which there are variable levels of motor recovery and, in most cases, central neuropathic pain syndromes (CNPs) develop several months to years after injury. Unfortunately, the study of chronic pain after SCI has been neglected due in part to the lack of appropriate animal models, but largely due to the clinically held belief that CNP is not a real phenomenon and is psychogenic in nature, rather than based on pathophysiologic mechanisms. The purpose of this study is to present standardized terminology of pain, offer insight into animal modeling issues of CNP, provide descriptions of the current clinical therapies, and examine the pathophysiologic mechanisms that provide the substrate for CNP that will lead to innovative new therapies. This information will provide new insights for health-care professionals for better care not only of SCI patients but also many other CNP syndromes. Key words: glutamate, excitatory amino acids, glutamate receptors, central sensitization.

Spinal cord injuries (SCIs) result in a devastating loss of function below the level of the lesion in which there are variable levels of motor recovery. In most cases, central neuropathic pain syndromes (CNPs) develop,1,2 usually within several months to years after the injury,1,3,4 which persist chronically or for life. In these patients, the pain so greatly affects the quality of life that they often suffer from depression and, in some cases, commit suicide.5,6 Research focused on improving recovery of function, including reduction of CNP, is essential. Unfortunately, the study of chronic pain after SCI has been neglected. A problematic issue for most SCI patients who have a CNP is that they are given psychiatric referrals, be-

cause it is generally believed that their pain is “all in their head,” which ignores possible pathophysiologic mechanisms that underlie the condition. Although advances have been made in the management of acute SCI through better patient management and aggressive rehabilitation,7,8 there has been little fruitful progress in understanding the pathophysiology of CNPs for the development of therapeutic approaches among SCI patients. However, recent advances in research in both animals and humans have provided insight into the pathophysiologic mechanisms that provide the substrate for CNPs, which are clearly not simply “psychiatric.”

From the Department of Anatomy & Neurosciences, University of Texas Medical Branch, Galveston, Texas, USA. Supported by the RGK Foundation, the Spinal Cord Research Foundation of the Paralyzed Veterans of America, the Kent Waldrep National Paralysis Foundation, the L. T. Hulsebosch Memorial Fund, Mission Connect of TIRR, and NIH Grants NS11225 and NS39161. Address reprint requests to Claire E. Hulsebosch, PhD, Department of Anatomy & Neurosciences, University of Texas Medical Branch at Galveston, 301 University Boulevard, Galveston, TX 77555-1043. E-mail: [email protected]. © 2003 Elsevier Inc. All rights reserved. 1537-5897/03/0103-0000/$30.00/0 doi:10.1016/S1537-5897(03)00039-9

Terminology in CNP Studies SCI with the development of various pain states continues to present a significant challenge for physicians treating these disease entities. Disturbingly little is known about the pathophysiology of pain after central nervous system (CNS) trauma. Clearly, attention devoted to the treatment of chronic central pain after SCI is underrepresented in terms of research and treatment options. The definition of central pain according to the International Association

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160 Seminars in Pain Medicine Vol. 1 No. 3 September 2003 for the Society of Pain is “pain initiated or caused by a primary lesion or dysfunction in the central nervous system”9; for example, pain that occurs after SCI. Chronic pain is that which persists beyond the period of wound-healing.10 Thus, chronic central neuropathic pain (chronic CNP) after SCI is pain that persists long after SCI-associated wound-healing. Central pain syndromes and dyesthesias (an unpleasant abnormal sensation that may or may not be painful) can be divided into two broad categories based on the dependency of the pain to peripheral stimuli: (1) persistent pain or dyesthesias, which occur independent of peripheral stimuli, occur spontaneously, and increase intermittently and can be described as numbness, burning, cutting, piercing, or electric-like11,12; and (2) peripherally evoked pain, which occurs in response to either a normally nonnoxious or noxious stimuli. In the case that the peripherally evoked pain is in response to a normally non-noxious stimulus, the pain state is considered allodynia. In the case that the peripherally evoked stimulus is in response to a normally noxious stimuli, but the response is exaggerated, the pain state is considered hyperalgesia. A subtle but important definition is the state of increased sensitivity to stimulation, which may or may not be painful, is considered hyperesthesia.9 Chronic central pain syndromes are characterized by the presence of persistent pain13,14 with concomitant changes in peripheral somatosensory responses.13

Taxonomy of Pain The International Association for the Study of Pain has recently proposed clear classifications for CNP after SCI, because there are clear differences with regard to kinds of pain presented in the clinic. An understanding of the pathophysiologic bases for these differences can aid in therapeutic strategies used to treat the pain.15,16 Essentially, there are two general classes of pain after SCI: nociceptive and neuropathic. Nociceptive pain is abnormal pain arising from stimulation of somatic or visceral nociceptors, whereas neuropathic pain is abnormal pain initiated or caused by a primary lesion or dysfunction in the nervous system.9 In SCI patients, examples of nociceptive pain include damage of skeletal structures and ligaments of the spine, overuse of muscles, and decubitus.15 Nonsteroidal anti-inflammatory drugs and physical therapy are effective treatment strategies for nociceptive pain. Neuropathic pain, however, remains a therapeutic challenge. If the lesion is in the peripheral nervous system, the

pain state is described as peripheral neuropathic pain; if the pain is in the central nervous system, the pain state is central neuropathic pain. Within the central neuropathic pain class, specifically in spinal cord lesions, there are three further subdivisions that describe the location of neuropathic pain relative to the location of the lesion: above-level, at-level, and below-level neuropathic pain. At-level pain is pain located in dermatomes immediately adjacent (typically rostrally) to the level of injury, most commonly described as a “girdle” of pain to mechanical stimuli. Below-level pain occurs in dermatomes or structures below the level of lesions commonly described by SCI patients as “my legs hurt.” Above-lesion pain is abnormal pain sensations that occur above the lesion such as increased sensitivity to tactile stimulation to the face of paraplegics and quadriplegics and increased sensitivity to cold. All three of these classifications, although described by location, are products of different pathophysiologic conditions, which, when understood, can be treated effectively.16,17 Another barrier to investigation of therapeutic strategies for treating CNP after SCI is the difficulty in modeling in mammalian models with similar pathophysiologic mechanisms to the patient population.

Modeling Pain There are several challenges with regard to modeling pain. For example, it is not possible to directly and objectively test the presence of pain in either human or animal subjects. Human patients often do not accurately describe subjective experiences, and it is impossible to test an animal model for a subjective, emotional experience. A fundamental question is: “Can central pain syndromes be investigated in animal models?” Animal models have the advantage that objective and unemotional responses can be measured reliably. In chronic central pain syndromes, the assumption is that changes in the level of activity of some portion of the nociceptive (pain) pathway occurs and persists chronically, and these changes result in changes in thresholds to stimuli from the periphery.13 The peripheral changes are clinically characterized by “overreactivity” to somatosensory stimulation, a condition that has been used as a classical clinical feature associated with central pain syndromes.18,19 Therefore, we conclude that when reflex threshold changes are accompanied by changes in whole-body posturing to avoid or stop further stimuli (avoidance posturing), vocalizations, writhing, and other behaviors consistent with the experience of a nociceptive stimulus (as observed in animal models), then the model becomes better val-

Central Sensitization and Pain After SCI

idated for pain studies. For instance, we empirically determined that 30 days after spinal hemisection or spinal contusion injury, animals became highly sensitive to handling; would turn and bite the handler, vocalize, and writhe; and would continue evoked behaviors consistent with the experience of nociceptive stimuli for weeks to months after surgery (until time of killing). Based on these observations, we carefully characterized the development of both mechanical and thermal hyperalgesia and allodynia that persisted for months, suggesting the value of these models for chronic pain studies.1,20 The failure of therapeutic strategies to treat dysesthesias of SCI is due in large part to two issues: (1) the lack of acknowledgment by the clinical community that CNP is “real,” and thus based on pathophysiologic mechanisms; and (2) the difficulty in modeling SCI in mammalian models with similar pathophysiologic mechanisms to the clinical symptomology. To our knowledge, there are only a few models of chronic pain after SCI: (1) the ischemic model, in which an intravascular photochemical reaction occludes blood vessels in the spinal cord, thereby producing spinal cord ischemia that results in a band of mechanical allodynia on the trunk at the lesion site (“girdle” region)21,22; (2) unilateral quisqualate injection into the low thoracic/lumbar spinal cord, which results in overgrooming and mechanical allodynia23; (3) the spinal contusion model, in which a weight is dropped onto the thoracic spinal cord resulting in changes in spontaneous activity,24 as well as thermal and mechanical allodynia in the limbs,20,25 and “girdle” allodynia20,26; (4) anterolateral lesions of the spinal cord in monkeys and rats that produce overgrooming and mechanical allodynia27,28; (5) spinal hemisection in rats that results in “girdle” allodynia, thermal and mechanical allodynia in forelimbs and hindlimbs,2 and alterations in spontaneous activity29; and (6) a clip compression model in which the thoracic spinal cord is compressed by a 35- or 50-g clip, wherein mechanical hyperalgesia is seen in the hindlimbs.30

Proposed Mechanisms of CNP Evidence that neurons in pain pathways are pathophysiologically altered and hyperexcitable, and thus exhibit central sensitization31 after SCI, comes from both clinical and animal literature. Perhaps the first widely cited example of spontaneous hyperactive and bursting neurons located in the spinal cord after SCI was described by Loeser et al32 in a patient with chronic pain. Their study suggested that the spontaneously hyperactive neurons might be the generator

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mechanism for the pain after various forms of deafferentation, such as brachial avulsions and SCI. In subsequent studies, spontaneous neuronal hyperactivity was reported in the thalamic nuclei of patients with chronic central pain syndromes,14,33 suggesting that spontaneous neuronal hyperactivity may be widely distributed throughout the somatosensory pathways. Research in animal models has shown that altered behavioral nociceptive states can be explained by a variety of nonexclusive mechanisms,7,8 and these have been speculated to contribute to central sensitization or permanent hyperexcitability of neurons in the pain pathways. The mechanisms proposed to lead to sustained central sensitization include: (1) prolonged and persistent firing of fine pain fibers from the periphery31,34; (2) spontaneous firing of sensory neurons in the dorsal root ganglia35,36; (3) increased sensitivity due to loss of nerve input (denervation supersensitivity37,38); (4) disinhibition or removal of inhibitory influences39-41; (5) increased efficacy of previously ineffective or “silent” synapses39,42; (6) anatomic alterations in the peripheral neural structure, such as increased sympathetic sprouting, which alter the response of sensory neurons to somatosensory stimuli43; (7) deafferentation hyperexcitability of spinal neurons and/or thalamic neurons14,33; (8) development of abnormal or overexpression of ion channels (ie, channelopathies) that alter the membrane properties of cells in the pain pathway44; (9) central neural structural alterations such as intraspinal sprouting of C and A-delta primary afferents45-49 or A-beta primary afferents50-54 that provide altered neuronal circuits as a substrate for maintained hyperexcitability of spinal neurons in the pain pathway; (10) alterations in transporter distribution and activity, such as those created by reversal of the glutamate transporters after SCI in which glutamate, normally removed from the extracellular environment, is transported from intracellular to extracellular spaces55; and (11) transmitter and/or receptor plasticity—that is, the upregulation or downregulation or change in receptor activation state as a result of SCI.41,56 All or combinations of the aforementioned mechanisms can alter second messenger systems, transcription factors, and a variety of cellular functions that could contribute to central sensitization and require broader approaches, such as DNA microarray analysis or proteomics.57 We hypothesize that another mechanism of the pain sequelae after SCI is triggered by excitatory amino acid (EAA) receptor–mediated development of hyperexcitability of spinal neurons in the pain pathways58,59, referred to as central sensitization.2,31,34,59 We hypothesize that central sensitiza-

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Fig 1. Schematically illustration (cf. Reference 64) of the variety of inputs onto projection neurons in nociceptive circuits. By inference, the diagram also illustrates the variety of receptors and ion channels that contribute to the membrane potential and to substances that can alter membrane potentials at points along the cell surface. Projection neurons are known to become hyperexcitable after SCI and, consequently, the resting membrane potential is altered, moving the potential closer to threshold. An understanding of the receptors and ion channels involved in the hyperexcitability allows appropriate therapeutic interventions (such as intrathecal delivery of appropriate antagonists or agonists to the “foci” that are hyperexcitable) to move the membrane potential (and, consequently, the nociceptive circuit) to preinjury potentials and reduce hyperexcitability. Site-specific deliveries of such compounds could be targeted at centers of hyperexcitability in the cord, or to ventral posterior lateral thalamus or higher centers, to attenuate the sensation of pain after SCI.

tion after SCI occurs initially as a result of the well-known increase in EAA extracellular concentrations,60-62 in turn activating EAA receptors, triggering changes that lead to alterations in transcription factors, increases in internal Ca concentrations, and changes in receptor activation state, all of which can contribute to maintained neuronal hyperexcitability.41,55,56,63 Thus, intervention administered acutely that intervenes in the conditions that establish central sensitization is a promising approach for prevention of CNP after SCI, areas that we are beginning to explore further. Studies in a variety of animal models have provided much insight into possible mechanisms and treatment strategies for CNP. Figure 1 shows a projection neuron in the pain pathway of the spinal cord (ie, a spinothalamic tract neuron) and input from primary afferents, interneurons, and descending inputs.64 In all three of these systems, putative transmitter substances either enhance or inhibit the excitability of the projection neurons by receptormediated alterations in membrane potential. Equally important in projection neuron excitability is the

presence of ion channels and a variety of second messenger and transsynaptic signaling cascades. Consequently, aberrant activation of one or more of these receptors and/or channels can produce sustained changes in the level of excitability. Thus, by pharmacologic interventions using antagonists of excitatory receptors, or agonists of inhibitory receptors or appropriate manipulation of ion-channel permeability, it is possible to alter the hyperexcitability present after SCI, once the channels are identified. Examples are given in what follows on the clinical progress as well as new opportunities as suggested by animal experiments.

Treatment Strategies for CNP—“Not All in Their Heads” Results of conventional neurosurgical treatment, such as lesions of the pain pathways, are generally disappointing in treatment of chronic central neuropathic pain after SCI. Approaches such as lesions of the spinothalamic pathways (the pain pathways),

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PERIPHERAL AND CENTRAL NEURONS A. Primary Afferents B. Descending Inputs C. Local Circuit Interneurons D. Non-Specific Targets E. Trans-Synaptic Signals

Transmitters: Glutamate and Aspartate Modulators: Substance P, Calcitonin Gene-Related Peptide, Vasoactive Intestinal Polypeptide, Neuropeptide Y Transmitters: Glutamate, Acetylcholine, Serotonin, Norepinephrine, Dopamine Modulators: Somatostatin, Substance P, Endorphin Transmitters: Glutamate, Aspartate, Glycine GABA, Acetylcholine Modulators: Somatostatin, Substance P, Enkephalin Vasoactive Intestinal Polypeptide Neuropeptide Y Ion channels (Na⫹, K⫹, Ca⫹⫹, Cl) Second Messengers Nitric Oxide, Carbon Monoxide, Prostaglandins

Fig 2. A listing of specific transmitters that can affect receptors on the projection neuron shown in Fig 1. Some nonspecific targets and transsynaptic signals that alter the membrane hyperexcitability are also listed.

dorsal root entry zone lesions (DREZ; lesions of the pain processing region in the spinal cord), and deep brain stimulation have largely been ineffective and may even aggravate central pain.15,65 Clinical trials with systemic administration of a variety of analgesic compounds have been inadequate for CNP after SCI. Within the last decade, recognition of the mechanisms of central sensitization contributing to the central neuropathic pain state have led to the successful utilization of nonopioid analgesics delivered by indwelling pump systems that deliver the agents to the intrathecal space (beneath the dura into the subarachnoid space) or given orally, with the latter systemic delivery having the disadvantages of acting on peripheral receptors and also producing sedation. Thus, an extremely promising approach would be to focus on the spinal administration of compounds to target the neuronal hyperexcitability in the spinal cord.66 Several compounds have proven somewhat successful when delivered intrathecally, either by continuous infusion or by bolus injection. Compounds such as lidocaine (nonspecific sodium channel blocker), morphine, clonidine (both ␣2-adrenergic agonists), and baclofen have demonstrated considerable efficacy in attenuating CNP symptoms for at- or below-level pain, but appear to be dose- and delivery-dependent, because not all clinical trials have reported comparable results.66 Baclofen, a GABAB receptor agonist, once used exclusively in the treatment of spasticity,67-69 and the anticonvulsant gabapentin (Neurontin, Parke-Davis), originally used to treat epilepsy, have had some success in the attenuation of musculoskeletal (baclofen) and chronic central pain syndromes (gabapentin).70-73 Gabapentin, a relatively new antiepileptic drug with few side effects and no known drug-to-drug interactions, is a structural analog of GABA that penetrates the blood– brain barrier, but does not act in the way it was originally designed—as a chemical drug-delivery system for GABA.74-78 The mechanism of gabapentin action in epilepsy is novel and may be related to its

binding capacity to the ␣2␦ subunit of the voltagedependent Ca2⫹ channel79; however, the mechanism of action remains unclear. Because central pain syndromes are thought to be due to excessive discharge of neurons in pain pathways, the use of antiepileptic drugs for the management of central pain is reasonable, particularly the new generation of compounds such as lamotrigine (a novel antiepileptic drug that acts at voltage-sensitive sodium channels).80,81 Intravenous deliveries of ketamine (an NMDA receptor antagonist) and alfentanil (a ␮-opioid receptor agonist) significantly reduced both the spontaneous and evoked component of CNP after SCI.82 The tricyclic antidepressant, amitriptyline, is effective in the treatment of dysesthetic pain,83 and is also being assessed in phase I clinical trials funded by the NIH. The mechanism of action by which amitriptyline produces analgesia is unclear, but may be related to inhibition of norepinephrine and serotonin reuptake or other actions.84 Oral tricyclic antidepressants are used for many chronic central pain syndromes, even those that are refractory to standard therapy, including narcotics,85 so results of amitriptyline trials seem promising. Few large clinical trials have been done in this area of study. One open clinical trial at the University of Pittsburgh, sponsored by the U.S. NIH–NICHD (clinicaltrials.gov), will report the effects of psychologic intervention and physical therapy in improving pain reduction. Another study, in partnership with Diacrin, Inc., and Washington University (http:// www.neuro.wustl.edu/sci/clinicaltrials.htm), is a phase I clinical trial in which porcine fetal neuronal cells are harvested from the lateral ganglionic eminence (LGE) and transplanted into the spinal cord for treatment of chronic pain. The LGE cells produce GABA-secreting cells that are lost in SCI. Because GABA can inhibit pain circuits,7 the hope is that the LGE cells will attenuate chronic pain syndromes. Overall, management of chronic pain after SCI is poor and remains a clinical challenge.

164 Seminars in Pain Medicine Vol. 1 No. 3 September 2003 To summarize, intrathecal or intravenous delivery modalities of some compounds have demonstrated success in CNP treatment after SCI, but few oral treatments are effective, with the possible exceptions of amytriptyline, gabapentin, and the newer antiepileptic drug, lamotrigine.86

Novel Treatment Strategies From Animal Studies Many of the animal SCI models address the at-level CNP that is also evident in patients. The spinal hemisection model,2 the spinal contusion model,20,25,26,87 the spinal ischemic model,88 and the quisqualic intraspinal injection model89 all produce mechanical allodynia or overgrooming at dermatomes that are immediately rostral or include the spinal segment that is the site of the central lesion. Pharmacologic interventions that have attenuated the at-level lesions include NMDA antagonists58,88 and administration of catecholamines by transplantation of adrenal chromaffin cells on the surface of the cord.90-92 Also found effective in at least one animal study is the intrathecal administration of either morphine or the adenosine A1 receptor agonist R-phenylisopropyl-adenosine.93 Interestingly, intrathecal opioid administration has been shown in other laboratories to exacerbate nociceptive responses,94 perhaps by activation of NMDA receptors95 or cholecystokinin-A receptors.94 The differences in results may be due to dose, unknown indirect pharmacologic actions, model issues (eg, age of animal, strain, gender) and so forth. In the spinal hemisection model, there is behavioral evidence for bilateral reorganization2,41 that represents the substrate for changes in somatosensation above-level in the forelimbs, at-level at the segment of spinal injury, and below-level in the hindlimbs. The contusion SCI models have severely compromised hindlimb behavior, so that belowlevel CNP cannot be evaluated. In the spinal hemisection model, the hindlimbs behaved similarly to the forelimbs, but the responses differ in absolute values. We previously reported a persistent state of hyperexcitability in dorsal-horn neurons recorded below the level of injury in the hemisection models both ipsilateral and contralateral to the injured side.2 Thus, membrane properties of wide dynamic range neurons in the spinal cord are changed permanently and dramatically. Intrathecal applications of compounds have been used to modulate specific membrane or ion-receptor populations. The effect of such manipulations on mechanical and thermal allodynia after spinal hemisection1 or contusion20,25,96 have been

examined. The hope is that, by characterizing the behavior and electrophysiologic properties of receptor/ion channel agonists and antagonists, more efficacious clinical treatments for CNP can be developed. As demonstrated in Fig 1, by pharmacologic interventions using antagonists of excitatory receptors, or agonists of inhibitory receptors or appropriate manipulation of ion-channel permeability, it is possible to alter the hyperexcitability present after SCI. Examples can be found of inhibition of peptide primary afferent transmission (CGRP antagonist97); inhibition of excitatory amino acid (EAA) receptors (NMDA antagonist, non-NMDA antagonist58); and application of exogenous catecholamines92 or serotonin,98 which are both found in descending inputs that provide tonic inhibition on projection neurons. Examples of attenuation of both evoked and spontaneous allodynia behaviors by administration of gabapentin have been demonstrated in the rat spinal hemisection model after development of mechanical and thermal allodynia.29 Behavioral measures of both mechanical and thermal allodynia have been described in detail elsewhere.1 Briefly, all aforementioned interventions resulted in attenuation of both mechanical and thermal allodynia, with the exception of the NMDA antagonist (D-AP5) and the nonNMDA antagonist (NBQX), which attenuated mechanical but not thermal allodynia. There is a significant body of work suggesting that interruption of the spinothalamic tract99 produces below-level neuropathic pain that is dependent on deafferentation of more rostral targets.27,28,100,101 This would explain the failure of similar types of surgery in the clinical population (see earlier). Abnormal firing patterns have been recorded in areas of the thalamus in both animals and SCI patients.14,33,102 Thus, therapeutic interventions that target central areas with heightened activity may be useful because it is probable that abnormal thalamic and/or cortical activity is associated with below-level phantom painlike syndromes. However, in the spinal hemisection model, transplants of nontumorigenic serotoninproducing cells onto the surface of the spinal cord near the lesion site produced a reduction in both mechanical and thermal allodynia in above- and below-lesion behavior, as well as attenuation of hyperexcitability of dorsal-horn neurons in the belowlesion region (above-lesion dorsal-horn neurons have not yet been tested), suggesting that attenuation of a focus or foci of hyperexcitability near the lesion site may be sufficient for successful attenuation of CNP behaviors.103 Because the acute pathophysiology of SCI includes a sudden increase in EAA concentrations,60-62 and acute intervention may alter the conditions that pro-

Central Sensitization and Pain After SCI

vide the basis for central sensitization, another promising approach to CNP treatment would be to use agents in the acute stages that would prevent the hyperexcitability from developing in the chronic stages of SCI. Specific EAA-subtype activation in the pathophysiology of excitotoxicity in SCI is beginning to be understood.60-62 The three major classes of EAA receptors are: (1) ionotropic non-NMDA receptors (selectively sensitive to AMPA or kainate); (2) ionotropic NMDA receptors (selectively activated by NMDA, and a voltage-gated ionic channel for cations); and (3) metabotropic receptors that are coupled to G-protein second messenger systems, which play direct roles in maintained hyperexcitability or central sensitization, a proposed mechanism for chronic central pain.31,34,104-106 NMDA, non-NMDA, and metabatropic EAA receptors are clearly major components of the SCI sequelae. After injection of NMDA,107 AMPA, and quisqualate, which is an agonist of both the metabotropic108,109 and AMPA glutamate receptors,110-112 histopathologic analyses in rodent SCI models have demonstrated the formation of spinal cavities similar to those observed in histopathologic studies of human SCI.23,56,107 In another study, blockade of the NMDA receptor with dextrorphan reduces the release of amino acids after spinal cord ischemia113; however, no behavioral or histologic assessment was done in that investigation. In addition, intraspinal or intrathecal injections of NBQX, an AMPA/kainate antagonist, after SCI resulted in a significant decrease in neural damage that was correlated with dose; that is, the greater the dose, the less tissue was damaged. The increased rescue of neural tissue corresponded to both increases in locomotor function and decreases in abnormal somatosensory scores.114,115 Thus, reduction in tissue loss after SCI improves outcome. In fact, studies in which dermatome CNP measurements were done2,20-23,107 indicate that the larger the lesion, the greater the area of at-level allodynia. Interventions that reduce lesion size should therefore improve functional outcome. In the case of SCI lesion–induced central sensitization, an increase in the activation state of EAA receptors may occur by a variety of mechanisms. The EAA receptor state may change, receptor upregulation may occur after SCI, or spinal circuit reorganization may contribute to increased excitability, any of which can nonexclusively contribute to hyperexcitability of spinathalamic tract cells (STT) cells. For example, activation of NMDA and AMPA/kainate receptors by EAA produces membrane depolarization, resulting in increased activation of NMDA receptors, which are voltage-gated, and an increased probability of an open channel state. Because the NMDA receptor is a divalent cationic channel, spe-

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cifically Ca2⫹, the increased open channel state results in Ca2⫹ influx intracellularly. EAA-mediated activation of the metabatropic glutamate receptor and increased intracellular Ca2⫹ levels result in activation of phospholipase C, which catalyzes the production of protein kinase C through the metabotropic glutamate receptor and the inositol-triphosphate pathway. Many subsequent pathways have been proposed for sustaining the NMDA receptor ionic channel open state and allowing increased calcium influx, which may result in maintained hyperexcitability or, if intracellular levels of Ca2⫹ are high, cell death.104,106 In the case of sustained central sensitization, such as that which occurs in CNP after SCI,2 the changes in secondary intracellular pathways are presumably sustained and maintain the hyperexcitability of the cell including both metabotropic and ionotropic glutamate receptors.24,104-116 Thus, the basis for neural excitability in CNP is shifted from ionotropic receptors to a combination of ionotropic and metabotropic glutamate receptor-mediated activation or sensitization. Therefore, to stop the development of CNP, both ionotropic and metabotropic glutamate receptors need to be explored. Furthermore, it should be noted that many blockers of the NMDA receptor are psychotomimetic, and therefore unsuitable for use in a conscious patient, as might be the situation after SCI. Substantial problems have been encountered with high-affinity, noncompetitive inhibitors (such as MK-801), and the fewest effects with blockers of the glycine-binding site and polyamine binding site and glutamate release blockers.117 Therefore, for maximum clinical relevance, we recommend studies of competitive blockers that offer a broader therapeutic window of efficacy. Short-term interventions in a rat spinal contusion model of agents that block metabotropic glutamate receptors, which represent the only G-protein-coupled excitatory amino acid receptor (the rest being ionotropic receptors), appear promising.24,56,63,116 CNP appears to be a product of a variety of mechanisms that contribute to a sustained and altered hyperexcitability of neurons in nociceptive circuits.32,118 Only two decades ago, the majority of treating physicians viewed CNP after SCI as a clinical entity suitable for psychiatric referrals, because the general belief was that there existed no pathophysiologic substrate that could adequately account for the persistent pain syndromes. We now have a few animals models, an early handle on therapeutic interventions that may be successfully applied clinically, and promising studies from well-designed clinical trials for CNP management after SCI based on data gleaned from animal studies.20,119 As neurosur-

166 Seminars in Pain Medicine Vol. 1 No. 3 September 2003 geons become more aggressive with early intervention techniques, we will be able to design preclinical animal trials for short-term intervention in the SCI population to rescue tissue in the peri-lesion area and prevent development of CNP. Finally, with the advent of molecular interventions, it is now possible to consider genetically engineered cellular delivery systems for eventual clinical delivery.120 Thus, in terms of incremental functional recovery of the patient population by advances in therapeutic interventions, resolving chronic central pain will be among the first dysfunctions to be “cured” after SCI.121.

Future Directions In the next few years, “stem cell” therapy will offer opportunities for cell replacement strategies, once the fundamental biology of these cells is known. Cell transplant strategies will be most useful when one or a few factors are missing; thus, chronic pain will benefit first in the current clinical trial applications. Two examples given earlier were the behavioral success of the catecholamine-producing adrenal chromaffin cells and the immortalized, nontumorigenic serotonin precursor cells in regions below the level of SCI, which were found to improve both locomotor and somatosensory function in animal studies90-92,103 and in clinical trials in terminal cancer pain patients.122,123 In addition, a promising new avenue for the prevention of CNP is early intervention in the inflammation pathway8,124-126 that would inhibit proinflammatory cytokines like interleukin-1␤ (IL1␤) and tumor necrosis factor-␣ (TNF-␣),57,125 and the prostaglandin pathway,124 by early application of selective inhibitors (eg, blockers of specific proinflammatory cytokine receptors) or compounds (ie, the new COX-2 inhibitors), which, unlike the nonspecifically acting nonsteroidal anti-inflammatory drugs, are targeted to inhibit specific enzymes.120 Finally, the application of DNA microarray analysis and proteomics will allow temporal assessment of large numbers of genes and proteins after SCI. As a result, more therapeutic opportunities will become available, as many genes, previously thought to be unimportant in the development of CNP, will now be able to be identified with these techniques. In addition, the consequence of therapeutic interventions on the expression levels of vast numbers of genes and proteins will be assessed easily and will allow easy prediction of efficacious treatments likely to have few contraindications. Because the injured spinal cord has a different molecular environment than an uninjured cord, it is necessary to apply techniques that give a large amount of information

aimed toward understanding the effect of a single intervention on gene expression.57 There is considerable work in progress in this area, but considerable work has yet to be done. The author thanks Debbie Pavlu for administrative support and Kathia Johnson for technical assistance.

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