Pain following spinal cord injury: pathophysiology and central mechanisms

Pain following spinal cord injury: pathophysiology and central mechanisms

J. Sandkiihler, B. Bromm and GE Gebhat-t (Eds.) Progress in Brain Research, Vol. 129 0 2000 Elsevier Science B.V. All rights reserved CHAPTER 32 Pai...

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J. Sandkiihler, B. Bromm and GE Gebhat-t (Eds.) Progress in Brain Research, Vol. 129 0 2000 Elsevier Science B.V. All rights reserved

CHAPTER 32

Pain following spinal cord injury: pathophysiology and central mechanisms Robert P. Yezierski * University

of Miami,

Department

of Neurological Surgery and The Miami Miami, FL 33136, USA

The condition of pain following spinal cord injury Painful sensations are a frequent and troublesome sequela of paraplegia and quadriplegia following partial or complete lesions of the spinal cord (see review Yezierski, 1996). The condition of pain following spinal cord injury (SCI) was first described over 100 years ago, and the origin of various SC1 pain syndromes is based on the nature of the lesion, neurological structures damaged, and secondary pathophysiological changes of surviving tissue (Beric, 1990; Bonica, 1991; Davidoff and Roth, 1991; Tasker et al., 1991). In spite of recent progress directed towards understanding the mechanism(s) of spinal injury pain, it still remains a major challenge for health professionals (Bonica, 1991; Yezierski, 1996; Eide, 1998). To understand the impact of spinal injury pain on the health care community one needs only examine a sampling of studies which report the incidence of painful sensations at a rate of 60-80% for all SC1 patients with nearly 40% reporting severe pain to the extent they would trade any chance of functional recovery for relief of pain (Nepomuceuno et al., 1979; Beric, 1990; Britell and Mariano, 1991; Tasker

* Corresponding author: R.F?Yezierski, University of Miami, Department of Neurological Surgery and The Miami Project, 1600 N.W., 10th Avenue, R-48, Miami, FL 33136, USA. Fax: + I-305-243-4427; E-mail: [email protected]

Project,

1600 N. W, 10th Avenue,

R-48,

et al., 1991; Levi et .al., 1995; Widerstrom-Noga et al., 1999). The prevalence of pain coupled with the number of new injuries each year underscores the challenge to develop new treatments for patients requiring pain management. Through the use of different experimental models, valuable insights related to the mechanism(s) responsible for the onset of pain following injury have been obtained (WiesenfeldHallin et al., 1994; Yezierski, 1996; Christensen and Hulsebosch, 1997). Continued use of these models will hopefully lead to the identification of appropriate therapeutic targets and the development of novel treatment strategies. In this chapter efforts will be made to review the results of experimental and clinical studies that provide insights into possible mechanism(s) underlying selected pain states following spinal injury. A special emphasis will be placed on studies related to central dysesthetic pain, perhaps the most disabling of all sensory complications associated with SC1 (Nepomuceuno et al., 1979; Tunks, 1986; Davidoff et al, 1987; Beric et al., 1988; Davidoff and Roth, 1991; Tasker et al., 1991). Pain of musculoskeletal, radicular, visceral, and psychogenic origins all play a significant role in the clinical sequela of spinal injury and are discussed elsewhere (Tunks, 1986; Britell and Mariano, 1991; Summers et al., 1991). Similarly the epidemiological and clinical characteristics of different SC1 pain syndromes have been previously reviewed (Tunks, 1986; Bonica, 1991; Davidoff and Roth, 1991; Nashold, 1991; Yezierski, 1996; Siddall et al., 1997; Rintala et al., 1998).

430

1’

Spinal Injury

] ----I *

Neurochemical

Anatomical

AAs (glutamate, GABA) ionic (Na+,Ca”, CI-) peptides (dynorphin, Sub P) 2nd messengers (cGMP, NO, c-fos, NFkB); cytokines (TNF, IL-ID) enzymes (calpain, PLAz, PKC)

I

necrosis, apoptosis, gliosis, demyelination, cytoskeletal damage, deafferentation, sprouting

Physiological 0

excitability,

RF, background

activity,

gain,

after

discharge

+

Clinical/Behavioral allodynia,

hyperalgesia,

pain

Fig. 1. Summary of components in the spinal injury cascade responsible for the onset of pain following injury. Evidence supporting the basic concept of this cascade follows from results of clinical studies as well as those obtained from the ischemic, lesion and excitotoxic models of spinal cord injury (see text). The four major components of the cascade (neurochemical, excitotoxicity, anatomical and inflammation) are represented as being interactive and collectively lead to changes in the physiological state of spinal and supraspinal neurons. The end point of the cascade is the onset of clinical symptoms, e.g., allodynia, hyperalgesia, and pain. Abbreviations: EAAs = excitatory amino acids; Sub P = substance P; cGMP = cyclic guanidine monophosphate; NO = nitric oxide; NFkB = nuclear factor kappa B; PKC = protein kinase C; TNF = tumor necrosis factor; IL-l,3 = interleukin-lg; PL.42 = phospholipase A2; iNOS = inducible nitric oxide synthase; COX-2 = cyclooxygenase-2; RF = receptive field.

One of the first things to consider when discussing potential mechanisms of pain following spinal injury is the initial sequence of events triggered by ischemic or traumatic insult to the cord. Obviously there is significant structural damage to the cord parenchyma leading to a reorganization of spinal and supraspinal circuits responsible for the integration and processing of sensory information. Ischemic or traumatic insult to the cord also brings about changes in the expression of intrinsic chemical systems responsible for maintaining the homeostatic balance between inhibitory and excitatory circuits. Equally important is the cascade of cellular events affecting signaling, transduction and survival pathways of spinal neurons. Collectively, these injury-induced effects have a profound impact on the excitability and background discharges of spinal sensory neurons which ultimately affect both evoked and resting sensibilities. It is noteworthy that many of the patho-

physiological changes described following spinal injury parallel descriptions of events thought to be responsible for the development of pain following peripheral nerve and/or tissue injury (Dubner, 1991; see also Moore et al., 2000, this volume). It was a result of this observation that a common central injury cascade was proposed for the initiation of pain-related behaviors following central or peripheral injury (Yezierski, 1996). This proposal is by no means novel, as Livingston (1943) was one of the first to advance the concept that different pain syndromes may share a common patbophysiology. The different components of this central cascade are shown in Fig. 1 and include anatomical, neurochemical, excitotoxic, and inflammatory events that collectively interact to influence the functional state of spinal sensory neurons leading to the onset of different clinical pain states (allodynia, hyperalgesia, pain).

431

Pathophysiology

of spinal cord injury

The most obvious pathological characteristics associated with traumatic or ischemic injury to the spinal cord include but are by no means limited to the dramatic loss of neurons, damage to surrounding white matter, astrocytic scarring, syrinx formation, and breakdown of the spinal blood brain barrier (Kakulas et al., 1990; Bunge et al., 1993a; see also Vierck and Light, 2000, this volume). Also contributing to the progression of tissue damage are secondary injury cascades that include excitotoxic and inflammatory processes (Young, 1987; Tator and Fehlings, 1991; Hsu et al., 1994; Regan and Choi, 1994; Bethea et al., 1998). Finally, with the aid of specific histological and immunohistological stains one can follow the temporal profile of glia activation (astrocytes, microglial) and the infiltration of macrophages and other inflammatory cell types. Up-regulation of messenger RNA for c-fos, TNF-alpha and dynorphin have also been described following SC1 (Yakovlev and Faden, 1994). From this discussion it should be clear that the pathological sequela of SC1 is by no means simple nor is it restricted to the site of insult as pathological consequences of SC1 have been observed throughout the full extent of the neuraxis (Brewer et al., 1997; Jain et al., 1998; Ness et al., 1998; Morrow et al., 1999). One of the initial consequences associated with stroke, hypoxia-ischemia and traumatic brain injury is the well documented excitotoxic effects of excitatory amino acids (EAAs) (Regan and Choi, 1994). Similarly, evidence supports the involvement of glutamate in the secondary pathology, including neuronal degeneration, cavitation and edema, of ischemic and traumatic spinal injury (Faden and Simon, 1988; Nag and Riopelle, 1990; Hao et al., 1991a; Yezierski et al., 1993; Wrathall et al., 1994). For this reason glutamate has been viewed as one of several putative chemical mediators contributing to the ‘central cascade’ of secondary pathological changes following spinal injury (Tator and Fehlings, 1991). Three lines of evidence support the role of EAAs in the destructive cascade initiated by SCI: (a) following traumatic or ischemic SC1 there are significant increases in tissue content of glutamate and aspartate (Panter et al., 1990; Simpson et al, 1990; Marsala et al., 1994); (b) EAA receptor agonists exacerbate the neurodegenerative effects of spinal injury (Faden and Simon, 1988; Nag

and Riopelle, 1990); and (c) MK-801 and NBQX, selective NMDA and non-NMDA antagonists, respectively, provide significant neuroprotection following SC1 (Gomez-Pinilla et al., 1989; Hao et al., 1991b; Wrathall et al., 1994; Liu et al., 1997). Although EAA contents rise to toxic levels for only a brief period following injury, this dramatic change in tissue content of endogenous signaling molecules is thought to trigger an injury cascade that includes the production of inflammatory cytokines, prostanoids, as well as the up and down regulation of cellular messengers and transcription factors that can severely compromise the anatomical and functional integrity of spinal neurons. The excitotoxic model of spinal cord injury In recent years a number of experimental models have been used in the study of SC1 (Bunge et al., 1993b; Lighthall and Anderson, 1994; Christensen et al., 1996), each with distinctive characteristics related to specific aspects of the human condition. An important feature of these models is that each is based on a critical component of the primary injury (e.g., trauma or ischemia). Two approaches used to study spinal injury pain include the photochemical (Wiesenfeld-Hallin et al., 1994) and hemisection (Christensen et al., 1996) models. The weight drop or contusion model is the oldest and most widely used model of SCI, but has only recently been used in studies related to the altered sensation following injury (Siddall et al., 1995, 1999). A final approach involves the use of selected spinal lesions to study the central mechanisms of injury-induced pain (Levitt, 1989; Vierck, 1991; Vierck and Light, 2000, this volume). All of these experimental strategies share the distinction of producing pathological and/or behavioral changes associated with human SCI, and each provides unique opportunities to study different aspects of the spinal and supraspinal mechanisms responsible for central pain of spinal origin. Although the contusion and ischemic models of SC1 share many pathological characteristics with the human condition, the extent of tissue damage produced in these models makes it difficult to evaluate specific neural substrates responsible for the onset of injury-induced abnormal sensations. For this reason an alternative approach was developed (Yezierski et al., 1993). Out of consideration for the well

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documented elevation of EAAs following SCI, the excitotoxic model was developed to simulate this chemical change and evaluate the involvement of non-NMDA receptors in the pathological sequela of SC1 (Yezierski et al., 1993; Liu et al., 1997). Extending the results of previous investigators (Pisharodi and Nauta, 1985; Nag and Riopelle, 1990; Urea and Urea, 1990) Yezierski and colleagues used the technique of intraspinal microinjection to evaluate the anatomical and functional consequences resulting from injection of the AMPA/metabotropic receptor agonist quisqualic acid (QUIS) (Yezierski et al., 1993; Yezierski and Park, 1993). Additionally, the precision of the intraspinal injection technique made it possible to evaluate the contribution of specific neuronal populations to different behavioral outcome measures. The results also showed that using different injection strategies (i.e., volume, depth), it was possible to produce graded patterns of neuronal loss in specific regions of the spinal gray matter (Yezierski and Park, 1993; Yezierski et al., 1998a). While the varied morphological changes following QUIS injections supported a role of non-NMDA mediated mechanisms in ‘secondary injury’, of special significance was the relationship between excitotoxic cell loss and the emergence of spontaneous and evoked pain behaviors commonly associated with models of chronic neuropathic pain (Levitt, 1985; Vierck, 1991; Zeltser and Seltzer, 1994; Siddall et al., 1995; Christensen et al., 1996). Although the pathological findings following

QUIS injections were believed to be initiated by excitotoxic events, the contributions of other components of the ‘central injury cascade’ cannot be ignored. For example, QUIS injections resulted in the activation of the nuclear factor-kappa B (NF-kB) family of transcription factors (Bethea et al., 1998), a critical step in the inducible regulation over 150 genes involved in inflammatory, proliferative and cell death responses of cells (Baeuerle and Baltimore, 1991; Kaltschmidt et al., 1993; Pahl, 1999). Examples of genes regulated by activation of NF-kB include those responsible for encoding tumor necrosis factor (TNF), enzymes for cyclooxygenase (COX-2), nitric oxide synthase (iNOS), and prostaglandin synthase-2, interleukins (IL) 6 and lb, dynorphin, and intercellular and vascular cell adhesion molecules (Baeuerle and Baltimore, 199 1; O’Neil and Kaltschmidt, 1997). Thus, the excitotoxic model originally developed to evaluate the pathological role of non-NMDA mediated events in spinal injury, led to the discovery of an interrelationship between excitotoxic and inflammatory components of injury, and a possible link with the regulation of genes that may play an important role in spinal sensory processing. Recently, a more detailed study related to the inflammatory component of the QUIS injury model has shown that following QUIS injections there is an upregulation of mRNA for cytokines (IL-lp, TNF-a), COX-2, iNOS as well as the death-inducing ligands TRAIL and CD-95 (Plunkett et al., 2000).

Fig. 2. The effects of quisqualic acid (QUIS) injections or sham surgery on responses to mechanical and thermal stimuli delivered to the hind paws. Animals were pre-tested over a period of 9-10 days prior to receiving intraspinal injections of 125 mM QUIS (A,C) or sham surgery (B,D). Animals received unilateral injections (1.2 ul) directed at the dorsal horn and intermediate gray (right side) in spinal segments ranging from T12 to L2. Post-injection testing commenced 8-10 days after surgery and continued for a period of 44 days. (A,B) Results of testing with mechanical stimuli delivered to the hind paws ipsilateral and contralateral to the side of QUIS injections (A) or following sham surgery (B). Each point on the graph represents the mean threshold for all animals on each day of testing. Error bars represent standard errors around the mean. Stimulus intensity in grams is represented on the y-axis and days pre- and post-injection/surgery on the x-axis. Statistical comparisons were made between the mean pre-injection baseline value and data obtained on each day of post-injection testing: * = P < 0.05. No significant differences were observed between pre- and post-surgery response thresholds in animals with sham surgery (B). (C) Results of the paw flick test assessing the sensitivity to a radiant heat stimulus delivered to the hind paws (same group of ten animals tested in A). During post-injection testing there was a significant decrease in withdrawal latencies to thermal stimulation (bilaterally). Each point on the graph represents the mean of three trials for all animals on each day of testing. Error bars represent standard errors around the mean. Time in seconds is represented on the y-axis and days on the x-axis. Statistical comparisons were made between the mean pre-injection baseline value and data obtained on each day of post-injection testing: * = P < 0.05. (D) Responses to the paw flick test following sham surgery for the same group of seven animals tested in (B). No significant differences were observed between pre- and post-surgery response latencies. (Reprinted with permission from Yezierski et al., 1998a.)

433

no post-injection paresis and/or paralysis of hind limbs). Initial responses evaluated over a two-week period during pre-injection testing were elicited by stimulus intensities of lo-35 g (mean baseline value 21.0 f 9.8 g). Following QUIS injections in spinal segments T12-L2 stimulus intensities required to elicit hind limb responses were significantly lower (1.5-8.0 g) than pre-injection values (Fig. 2A). The time course for the onset of mechanical allodynia

Behavioral consequences of excitotoxic spinal injury Mechanical hypersensitivity

The evaluation of animals to varying intensities of mechanical stimuli was carried out in animals meeting inclusion criteria for behavioral testing (i.e., no signs of early excessive grooming behavior and

MECHANICALTEST 40. 36.

3 +

Len RQhl

32. 28;

Days

THERMALTEST

I

434 was IO-12 days. A control group of seven animals undergoing sham surgeries had pre-surgery response thresholds similar to the pre-injection values of QUIS animals (17.9 f 4.4 g) and showed no significant change in stimulus intensity required to elicit responses throughout the post-surgery evaluation period (Fig. 2B). Animals evaluated for responses to mechanical stimuli were followed for a period of 34 days post-injection. The fact that significant effects (relative to baseline) were observed throughout this time period (with no signs of recovery) underscores the chronic nature of the behavioral effect. Responses to thermal stimuli Responses to the Hargreaves et al. (1988) thermal detection task were evaluated in the same animals undergoing mechanical testing. Differences in responses to thermal stimulation were found starting approximately IO-12 days post-QUIS injections and lasted throughout the evaluation period of 34 days. Pre-injection withdrawal latencies averaged 13.2 f 0.8 s while post-injection values were in the range of 8-l 1 s. As with mechanical stimulation, thermal stimuli were delivered to the glabrous skin of the hind paws in animals receiving QUIS injections in spinal segments Tl2-L2. Thus, responses reflecting a hypersensitivity to thermal stimulation were observed in dermatomes remote from those represented by segments receiving QUIS injections. Similar to the results with mechanical testing no preferential effects were observed between left and right hind paws (Fig. 2C). A control group of seven animals undergoing sham surgeries had pre-surgery response latencies similar to pre-injection values of QUIS animals (13.2 f 0.2 s) and showed no significant changes in response latencies throughout the post-surgery evaluation period (Fig. 2D). Efforts to correlate the pattern of neuronal loss with thermal and mechanical hypersensitivity proved unsuccessful; no such correlation was found with the onset of thermal hyperalgesia or mechanical allodynia. In fact, the results support the conclusion that animals with neuronal loss anywhere in the superficial or deep dorsal horn could be expected to exhibit changes, albeit not of the same magnitude, in thermal and mechanical sensitivity. Furthermore, it is of special significance that the behavioral responses to

mechanical and thermal stimuli were evaluated in the hind paws (following injections in spinal segments Tl2-L2). These results suggest that the effects of injury are distributed several segments (and bilaterally) from the site of injection. The fact that all animals exhibited bilateral changes in sensitivity (some without obvious signs of contralateral neuronal loss) indicates that the effects of unilateral injury are distributed along both sides of the cord. These results are not surprising given the complexities of propriospinal connections and the likely involvement of propriospinal circuits in the distribution of descending influences (see also Pertovaara, 2000, this volume) from bulbospinal pathways. Excessive grooming behavior Beginning on the second day post-QUIS injection animals were inspected daily for signs of excessive grooming (e.g., removal of hair, superficial skin damage). Based on results in over 100 animals this behavior typically targets dermatomes associated with spinal segments at or caudal to the site of QUIS injections (Yezierski et al., 1993, 1998a). Excessive grooming behavior is a progressive condition and therefore a classification scheme for different phases of this behavior was developed: (a) Class I, hair removal over contiguous portions of a dermatome; (b) Class II, extensive hair removal combined with signs of damage to the superficial layers of skin; (c) Class III, hair removal and damage to dermal layers of skin; and (d) Class IV, subcutaneous tissue damage (experiment terminated). Excessive grooming behavior was correlated with a lesion sparing the superficial laminae of the dorsal horn and is viewed as a variant of the well described ‘deafferentation autotomy’ (Yezierski et al., 1998a). Support for the conclusion that activity in the superficial dorsal horn may contribute to this behavior was found in animals with injections selectively eliminating different regions of the gray matter. Examples of neuronal loss consistent with the conclusion that the superficial dorsal horn ipsilateral to the site of grooming is important in the onset of excessive grooming behavior are shown in Fig. 3. Fig. 3A shows a cord where the superficial region and neck of the dorsal horn on the side of injection were eliminated and this animal did not

435

Fig. 3. Patterns of neuronal loss following intraspinal injection of 125 mM quisqualic acid (QUIS). All injections were made on the right side of the spinal cord. (A) Neuronal loss throughout the dorsal horn following injection of 0.6 pl of QUIS at a depth of 300 urn in spinal segment L2 (survival period 30 days). (B) G rooming-type damage represented by neuronal loss in the neck of the dorsal horn (arrows) following injection of 0.6 ~1 of QUIS at a depth of 900 urn in spinal segment T13 (survival period 32 days). (C) Neuronal loss throughout the dorsal horn (ipsilateral to injection) and in the neck of the dorsal horn (arrows) contralateral to injection site (L4) where 1.2 pl of QUIS was injected at depths of 600 urn and 1200 urn (survival period 18 days). The pattern of neuronal loss contralateral to injection represents grooming-type damage. (D) Bilateral grooming-type damage represented by neuronal loss in the dorsal horn partially sparing the superficial laminae (arrowheads) following injection of 1.2 ~1 of QUIS at depths of 600 urn and 1200 pm in spinal segment T13 (survival period 34 days). (E) Bilateral grooming-type damage represented by neuronal loss throughout the neck of the dorsal horn following injection of 1.2 ul of QUIS at depths of 600 urn and 1200 urn in spinal segment Ll (survival period 27 days). Note partial and complete sparing of the superficial laminae (arrowheads) ipsilateral and contralateral, respectively, to injection site. (F) Bilateral grooming-type damage represented by neuronal loss below the superficial laminae ipsilateral and contralateral following injection of 1.2 ul of QUIS at depths of 600 pm and 1200 urn in spinal segment L3 (survival period 28 days). Note sparing of superficial laminae (arrowheads) contralateral and ipsilateral to the site of injection. Scale bar in (E) equals 190 urn in (A-C), (E-F) and 320 urn in (D). (Reprinted with permission from Yezierski et al., 1998a.)

exhibit excessive grooming behavior (30 days survival). By contrast, the pattern of neuronal loss in Fig. 3B included the neck of the dorsal horn with sparing of the superficial region. This animal exhibited excessive grooming behavior ipsilateral to the side of neuronal loss. This pattern of neuronal loss is referred to as ‘grooming-type damage’. Results com-

parable to those in Fig. 3B were found in nearly 90% of animals with excessive grooming behavior. Also supporting our conclusion were animals with extensive neuronal loss throughout the superficial and deep laminae of the dorsal horn ipsilateral to injection sites and additionally had neuronal loss on the contralateral side of the cord restricted to the neck

436

of the dorsal horn (Fig. 3C). These animals exhibited excessive grooming behavior targeting skin regions contralateral to the injection site. Finally, animals exhibiting bilateral grooming behavior typically had bilateral grooming-type damage that included damage to the neck of the dorsal horn with partial or complete sparing of neurons in the superficial laminae (Fig. 3D-F). While the onset of self-directed behaviors have been described following lesions of the spinal cord (Frommer et al., 1977; Levitt, 1985), the results following QUIS injections were the first to have a dermatomal relationship that correlated with an injury site restricted to the gray matter of the spinal cord. Although the clinical relevance of autotomy has been controversial (Rodin and Kruger, 1984; Levitt, 1985; Coderre et al., 1986), Mailis (1996) described compulsive, self-injurious behavior (SIB) in humans with neuropathic pain. In this study it was concluded that “. . compulsive targeted self-injurious behavior in humans with neuropathic pain and painful dysethesiae is consistent with the concept that animal autotomy may result from chronic neuropathic pain after experimental peripheral or CNS lesions”. As discussed by Vierck (1991; see also Vierck and Light, 2000, this volume), however, the presence of self-directed behaviors (e.g., autotomy or excessive grooming behavior) does not necessarily support the conclusion that pain is the eliciting stimulus. These behaviors could be generated by paresthetic sensations or dysesthesias. Regardless of the eliciting stimulus when these behaviors are present, it is not unreasonable to conclude that they reflect the presence of an abnormal sensation. Without exception excessive grooming behavior targets peripheral dermatomes associated with spinal segments at or adjacent to the site of injury (Fig. 4). This distribution, in general, coincides with the dermatomal map described in the rat (Takahashi and Nakajima, 1996). Of special interest in QUIS-injected animals is the parallel between the delayed onset of excessive grooming and a similar temporal profile of central pain in patients with SCI. QUIS-induced excessive grooming is also similar to the behavioral agitation described by Yaksh (1989) following intrathecal administration of strychnine and bicuculline, where animals bite and scratch themselves after injections of these inhibitory amino

Fig. 4. Topographic distribution of areas targeted for excessive grooming behavior as a function of spinal segments injected with quisqualic acid (QUIS). Excessive grooming behavior is directed towards skin areas in dermatomes represented by spinal segments at or caudal to those receiving QUIS injections. The areas outlined on the line drawing summarize the location of all areas affected by excessive grooming behavior (Class IIV) following injections in segments shown in the inset. As injection sites move from rostra1 (TlO-Tll) to caudal (L3L4), the location of sites target for excessive grooming behavior move down the body from thoracic to hind limb dermatomes. (Reprinted with permission from Yezierski et al., 1998a.)

acid antagonists. In many respects the biting and scratching is also similar to that observed following intrathecal injections of substance P, somatostatin, or alumina gel (see references in Levitt, 1985). The similarity between QUIS-induced excessive grooming behavior and pain behaviors following intrathecal injection of these substances suggests that the central mechanism responsible for these behaviors involves disruption of local inhibitory pathways and/or the emergence of abnormal ‘focal generators’ within the injured cord (see below). In conclusion there are three important similarities between excessive grooming behavior and the well documented clinical condition of junctional pain in patients with spinal injury: (a) delayed onset; (b) spontaneous nature; and (c) dermatomal distribution relative to site of injury. The delayed onset of excessive grooming behavior suggests that the neural mechanism is not simply an inhibitory release phenomenon, but instead requires significant changes (over time) in the functional state of spinal (and possibly supraspinal) sensory neurons. It is hypothesized that this behavior may be due to a loss of spinal nociceptive neurons, thus creating an imbalance between normal gating and biasing mechanisms within spinal and supraspinal somatosensory pathways (Melzack

437 and Loeser, 1978). Combined with a loss of segmental and/or supraspinal inhibitory influences, spinal neurons become hyperactive and these focal pattern generators are responsible for producing paraesthetic and/or dysesthetic sensations referred to the affected dermatome. Functional correlate of behavioral changes following excitotoxic spinal cord injury Evaluation of a possible neural correlate of QUISinduced behavioral changes was undertaken by examining the functional properties of dorsal horn neurons, including cells belonging to the spinomesencephalic tract (SMT). Supportive of a spinal mechanism for the evoked and spontaneous behavioral changes following QUIS injections was the finding that spinal neurons adjacent to the injury site undergo significant functional changes, including a shift to the left in the stimulus-response function, an increase in the level of background activity, and an increase in the duration of afterdischarge responses following removal of a stimulus (Yezierski and Park, 1993). The fact that these changes were observed in cells belonging to the SMT supported the notion of a possible surpraspinal component to the observed pain behaviors, the fact that cells had peripheral receptive fields overlapping with areas targeted for excessive skin grooming supports the contention that this behavior is not related to an insensate area/region of skin. Changes in the response characteristics of spinal neurons similar to those observed following QUIS injuries have been reported for cells following ischemic (Hao et al., 1992) and hemisection (Hulsebosch et al., 1997) injury of the spinal cord. In the excitotoxic model these changes appeared within 47 days of injury and were especially prevalent in animals with excessive grooming behavior. Afterdischarges lasting 5-15 min and ‘wind-up’ of background discharges with repeated stimulation were novel characteristics of neurons in QUIS-injected animals. The increased excitability, bursting discharges, and long afterdischarge responses of neurons in QUIS-injected animals are reminiscent of the abnormal functional characteristics of neurons recorded in patients with chronic pain following SC1 (Loeser et al., 1968; Edgar et al., 1994). Elimination

of this activity by computer-assisted DREZ (dorsal root entry zone) results in a significant reduction of spontaneous pain. Further supporting the hypothesis of a spinal pain generator are results showing that local anesthetic applied to the proximal stump of a spinal transection results in transient relief of pain (Pollock et al., 1951). Spatial profile of spinal cord damage required for the onset of pain behaviors following excitotoxic spinal injury In initial studies evaluating the behavioral consequences of QUIS-induced spinal injury little attention was given to the longitudinal extent of neuronal loss required to produce these behaviors. While it is acknowledged that the cellular and molecular events accompanying injury are undoubtedly important in inducing pain behaviors, we asked the question if the longitudinal extent over which neurons are affected by the injury process is also important. To this end we carried out an analysis of the number of sections with grooming-type damage (as determined from counts of cresyl violet stained sections) in animals with and without excessive grooming behavior. The results suggested that there exists a critical extent of damage along the rostrocaudal axis of the cord which is required to precipitate the onset of this spontaneous pain behavior. The evaluation of Long Evans (LE) (n = 19) and Sprague-Dawley (SD) (n = 69) rats consistently showed that there was a significant difference in the extent of groomingtype damage between grooming and non-grooming animals. In animals with injury-induced grooming behavior the longitudinal extent of grooming-type damage was 5175 urn (SD) and 5400 urn (LE). By contrast, damage in non-grooming animals was 3375 urn (SD) and 3750 urn (LE). Based on these data a hypothetical model of tissue damage versus pain behavior is proposed (Fig. 5). In this model there is a gradual progression of cord damage (including the influence of cellular and molecular changes) away from the injury epicenter. As the injury evolves the extent of tissue damage approaches threshold, triggering the onset of pain behaviors. This model implies that it is not only the injury cascade per se that is responsible for the onset of central pain following spinal injury. but the longitudinal extent over

THRESHOLD FOR PAIN BEHAVIOR

Fig. 5. Hypothetical progression of the central injury cascade from the epicenter (EPZ) of an ischemic, traumatic or excitotoxic insult to the spinal cord. In this model the extent of injury and/or the area of cord influenced by different components of the injury cascade expands to include 2” and 3” areas of injury. - . If left untreated the amount of cord damage will continue to expand until it exceeds the threshold required for the onset of pain behavior.

which these events influence neurons is also important. Although a fundamentally simple concept, these results suggest that limiting the amount of neuronal damage either by neuroprotective or rescuing strategies could have a beneficial effect as an intervention in the treatment of spinal cord injury pain. To test the above hypothesis rats were injected with QUIS and simultaneously administered intraperitoneal injections of the NMDA antagonist and NOS inhibitor agmatine. Agmatine is a cationic amine formed by the decarboxylation of arginine. It interacts with various neurotransmitter receptors including nicotine, NMDA, alpha2-adrenergic, and imidazoline. The fact that agmatine has biological activity as an antagonist of the NMDA receptor and inhibitor of NOS led to the proposal that it meets many criteria for a neurotransmitter-neuromodulator (Reis and Regunathan, 1998). In previous studies agmatine was shown to be neuroprotective following ischemic injury in the brain and following traumatic and excitotoxic injury in the spinal cord (Gilad et al., 1996; Yezierski et al., 1998b; Yu et al., 2000). Additionally, agmatine has beneficial effects on pain behaviors in the dynorphin model of chronic allodynia, Chung model of spinal nerve ligation, carrageenan-evoked muscle hyperalgesia and the CFA model of hyperal-

gesia (Fairbanks et al., 2000). We have shown that agmatine administered at the time of QUIS injury delays or prevents the onset of excessive grooming behavior (Fig. 6).The results of a 16day treatment with agmatine (100 mg/kg, i.p.) showed that over a survival period of 40 days the final area of skin involvement targeted for excessive grooming was significantly reduced (Fig. 6A), the onset time of spontaneous grooming was significantly increased (Fig. 6B), the severity of grooming behavior was significantly lower (Fig. 6C), and the longitudinal extent of grooming-type damage was significantly less than in animals treated with saline (Fig. 6D). Neuroprotective effects similar to those with agmatine have also been obtained with the potent antiinflammatory IL-10 (Brewer et al., 1999). In this study a one time systemic injection of 5 pg of IL-10 significantly reduced neuronal loss in the excitotoxic model of injury. These results are consistent with a study showing the neuroprotective and behavioral effects of IL-10 following traumatic spinal cord injury (Bethea et al., 1999a). To determine if there was a behavioral correlate to the neuroprotective effects of IL-10 in the QUIS model we tested IL-10 against QUIS-induced excessive grooming behavior. The results of this evaluation showed that IL-10 significantly increased the onset time and reduced

439

FINAL

AREA

OF SKIN

DAMAGE

ONSET

OF GROOMING

C

GROOMING

GROOMING DAMAGE IN THE DORSAL HORN

SEVERITY

A: Q-Groom+Ag C: QUIS+Ag

Ll

(n=8) (n=7)

B: Q-Groom+Saline D: QUIS+Saline

(n=8) (n=8)

Fig. 6. Effects of agmatine treatment on excessive grooming behavior following excitotoxic spinal cord injury. (A) Final area of skin damage caused by excessive grooming behavior. (B) Onset time for the start of excessive grooming behavior following the intraspinal injection of quisqualic acid (QUIS). (C) Final classification of excessive grooming behavior, i.e. severity of grooming, following intraspinal injection of QUIS. (D) Longitudinal extent of grooming-type damage in the spinal gray matter following the intraspinal injection of QUIS. The type of treatment and number of animals in each group is indicated in the inset at the bottom of the figure. (A) QUIS-induced grooming plus agmatine treatment (100 mg/kg, i.p., 14 days). (B) QUIS-induced grooming plus saline treatment. (C) QUIS injection plus agmatine treatment (100 mg/kg, i.p, 14 days). (D) QUIS injection plus saline treatment (see text for details). ** = P < 0.01 (A) versus (B); ### = P < 0.01 (C) versus (D).

the area of excessive grooming behavior following QUIS injections (Bethea et al., 1999b). The effect of IL-10 on the QUIS-induced pain behavior is consistent with the effects of IL-10 on dynorphin-induced allodynia (Laughlin et al., 1999). The fact that agmatine and IL-10 can be used effectively as preventive treatments for injury-induced pain behaviors underscores the potential of these therapeutic interventions as preemptive strategies of pain management (see also Jensen and Nikolajsen, 2000, this volume) for

patients predisposed to progressive tissue damage in the spinal cord (e.g., syringomyelia, spinal cord injury). The above studies with agmatine and IL-10 lend support to the ‘neuroprotective hypothesis’ of SC1 pain, but of greater importance and potential clinical relevance, agmatine is also an effective treatment for the progression of injury-induced excessive grooming behavior (Fig. 6A,C,D). Similar results have also been obtained with IL-10 (data not shown). These

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results further underscore the importance of inflammatory mediators, NMDA receptors and nitric oxide in influencing the functional state of spinal neurons. Agmatine (100 mg/kg, i.p.) administered at the time of grooming onset significantly reduced the final area of skin damage, the severity of grooming, and the extent of grooming-type damage in the spinal cord. These results are similar to those obtained with transplantation of adrenal medullary tissue which was also found to reverse the progression of excessive grooming behavior (Brewer and Yezierski, 1998). Adrenal chromaffin cells are known to produce a wide array of potentially analgesic agents including the NMDA antagonist histogranin and neurotrophic and growth factors including FGF-2 and TGF-l3 (Sagen, 1996; Brewer and Yezierski, 1998). These results are encouraging as they suggest that it is possible to ‘turn down’ an ongoing pathological process over a critical length of the cord and retard or reverse an ongoing pain behavior. The exact nature of this ‘process’ and the precise therapeutic target(s) remain the focus of future investigation.

In addition to the above results obtained with the excitotoxic model of spinal injury a number of other mechanisms have been proposed to explain the onset of pain following injury. A brief review of these mechanisms is presented below. Over the past 40 years a number of mechanisms have been proposed to explain the condition of central pain following SCI: (a) loss of balance between different sensory channels (Beric et al., 1988); (b) loss of spinal inhibitory mechanisms (Melzack and Loeser, 1978; Wiesenfeld-Hallin et al., 1994); (c) the presence of pattern generators within the injured cord (Pollock et al., 195 1; Melzack and Loeser, 1978; Yezierski and Park, 1993) or supraspinal relay nuclei (Lenz et al., 1991); and (d) synaptic plasticity (see also Gerber et al., 2000, this volume; Moore et al., 2000, this volume; Sandktihler et al., 2000, this volume).

classic pain transmission system in the anterolateral quadrant of the cord can play a significant role in the onset of dysesthesia pain. This paradox has been discussed previously (Kendall, 1949; Boivie, 1992; Pagni, 1998). In the studies by Beric and colleagues, preservation of the modalities of touch and vibration (i.e., dorsal column function) in the absence of pain and temperature sensibilities (i.e., spinothalamic function), combined with evoked potential studies consistent with these findings, were common in SC1 patients with dysesthetic pain syndrome (Beric, 1988, 1992). As a result it was proposed that an imbalance in sensory information conveyed by the dorsal column medial lemniscal (DCML) and anterolateral systems (ALS) has an important role in post-traumatic central pain. The paradox of this hypothesis lies in the fact that disruption of pathways in the anterolateral quadrant of the cord has historically been used to eliminate chronic pain (Pagni, 1998). Dysesthetic sensations, however, may occur following spinothalamic tractotomies directed at the spinal or mesencephalic trajectories of these pathways (Pagni, 1998). In fact, severe spinal lesions with total destruction of ascending sensory systems are usually not followed by pain syndromes, but mild, moderate or severe disruption of the ALS with partial or complete sparing of the DCML pathway is most frequently associated with central pain. Additional support for the ‘imbalance hypothesis’ comes from reports of stroke patients with pain or dysesthesia. These patients invariably have an absence of anterolateral sensibilities coupled with preserved dorsal column function (Boivie and Leijon, 1991). Pagni (1998) concluded that lesions of the spinothalamic system intended to relieve pain regardless of level may sometimes produce new pains or aggravate existing pains. In view of these clinical reports it was proposed that dysesthesias following SC1 result from the central misinterpretation of residual dorsal column input which functions in the absence of suppression via an integrated spinothalamic tract system (Beric et al., 1988; Tasker et al., 1991).

Imbalance of sensory pathways

Loss of inhibitory tone

Perhaps the most intriguing of the above hypotheses evolved from the observation that damage to the

A critical factor in the onset of pain-like behaviors following SC1 is believed to be a loss of inhibitory

Mechanism(s) of pain following spinal injury

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tone within the injured spinal cord (WiesenfeldHallin et al., 1994). The loss of spinal inhibitory control would allow for the recruitment of surrounding neurons and the intensification and spread of abnormal sensations, including pain. Support for this conclusion comes from four lines of evidence: (a) following ischemic injury there is an increased excitability of WDR neurons that is reversed by the GABAs receptor agonist baclofen (Hao et al., 1992b); (b) hypersensitivity to peripheral stimuli can be produced in normal animals by the intrathecal administration of GABA receptor antagonists (Yaksh, 1989; Hao et al., 1994); (c) there are decreased numbers of GABA-positive neurons following ischemic spinal cord injury (Zhang et al., 1999); and (d) administration of drugs that prolong the action of inhibitory neurotransmitters (i.e., cyclic antidepressants) are effective in the short-term treatment of spinal injury pain (Tunks, 1986; Leijon and Boivie, 1991; Boivie, 1994). Although existing evidence supports the decreased inhibitory influence of GABAergic neurotransmission in altering the functional properties of neurons in the injured cord, not to be overlooked in this process is a decreased influence of supraspinal and propriospinal inhibitory pathways that may be disrupted following injury. An important response (in brain and spinal cord) following ischemia and trauma is an increase in tissue content of glutamate. Given the well documented involvement of NMDA receptors in altering the excitability of spinal neurons (Haley and Wilcox, 1992; Woolf, 1992) it is reasonable to propose, along with a failed GABAergic inhibitory system, that increased NMDA receptor activation (secondary to injury-induced release of glutamate) could play a role in the cascade of physiological and behavioral changes following spinal injury. Blockade of acute allodynia by the competitive NMDA receptor antagonist MK-801 provides support for this hypothesis (Hao et al., 1991a). Relevant to this discussion is the clinical report of Eide et al. (1995) showing that central dysesthesia pain after traumatic spinal cord injury is dependent on NMDA receptor activation. Pattern generators of pain Another component of the pathophysiological sequela of SC1 which is thought to contribute to the

onset of altered sensations is the emergence of a ‘pattern generating mechanism’ (spinal and supraspinal). Evidence supporting this hypothesis led Melzack and Loeser (1978) to conclude that not all postinjury pains are due to noxious input; some may be due to deafferentation and/or loss of inhibitory control and subsequent changes in the firing patterns, including burst activity and long afterdischarges of neuronal pools lying adjacent to a site of injury. Loss of inhibitory control (spinal and supraspinal) is an important component of this model, allowing for the recruitment of surrounding neurons and the intensification and spread of pain. Several observations are consistent with the ‘pattern generating’ hypothesis: (a) the existence of abnormal focal hyperactivity in the spinal cord and thalamus of spinal injured patients (Loeser et al., 1968; Lenz, 1991; Edgar et al., 1994); (b) the effectiveness of spinal anesthesia in alleviating pain when delivered proximal to the site of injury (Pollock et al., 1951; Botterell et al., 1953); and (c) abnormal responses and prolonged afterdischarges of spinal sensory neurons following experimental SC1 (Hao et al., 1992a; Yezierski and Park, 1993; Christensen and Hulsebosch, 1997). Consistent with the excitability hypothesis and the involvement of neurons in the superficial dorsal horn in spontaneous and evoked pain behaviors, are clinical reports of abnormal focal hyperactivity within the superficial laminae of the injured cord (Edgar et al., 1994). In this report it was concluded that the origin of post-traumatic central pain is in the dorsal root entry zone (DREZ) at depths of l-2 mm, representing Rexed’s laminae I-II. Microcoagulation of these hyperactive areas results in a significant diminution of pain. A variant of the DREZ technique utilizing intramedullary recordings of C-fiber evoked responses to guide DREZ lesioning was recently described (Falci et al., 1999). This technique allows for the somatotopic mapping of the DREZ with regard to the generation of central deafferentation pain. In 25 patients where this technique was used, 84% received complete pain relief. Local anesthetics (which shut down local ectopic activity) delivered to the spinal cords of SC1 patients with dysesthetic pain syndrome also result in the temporary relief of pain (Pollock et al., 1951; Botterell et al., 1953). Two recent reports are consistent with the involvement of the superficial laminae in the persistence of neuro-

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pathic pain (Malmberg et al., 1997; Mantyh et al., 1997). Thus, the superficial dorsal horn may be important not only in the onset but also the progression of neuropathic pain following SCI. Although changes in the excitability and response properties of spinal sensory neurons are thought to be important in the central response to XI, another aspect of the central injury cascade that should not be ignored is the involvement of supraspinal structures (e.g., diencephalon). The contribution of abnormal spinal input together with the effects of deafferentation (secondary to loss of spinal projection neurons) could result in the development of abnormal generators at supraspinal sites (Lenz, 1991; Vierck, 1991; see also Lenz et al., 2000, this volume). Hyperactive neuronal activity in thalamus and cortex of rats exhibiting extensive self-directed behavior following dorsal rhizotomy (Lombard et al., 1979), and the onset of autotomy following injections of epileptogenic agents into the mesencephalic central gray matter in cats (Black, 1974), provide additional support for the view that changes in the excitability of supraspinal neurons play a role in the onset of pain behaviors following peripheral and/or central injury. Recently, the report of elevated blood flow in thalamic nuclei (possibly reflecting changes in the functional state of neurons) lend further support to a thalamic involvement in the supraspinal response to SC1 and to the mechanism of injury induced pain (Morrow et al., 1999). Synaptic plasticity A final consideration for the mechanism of chronic pain following spinal injury is synaptic plasticity. A significant response to injury of central or peripheral origin is the cellular response believed to contribute to the sensitization of spinal neurons. Synaptic plasticity in the CNS is clearly a part of the central sensitization underlying acute pain, and together with the long-term changes in spinal connectivity represent a potential mechanism for persistent pain (see also Moore et al., 2000, this volume). Unfortunately, we are only at the beginning of understanding the biochemical, molecular and functional events underlying long-term plasticity and its role in the clinical condition of chronic pain. Included in the events thought to be involved in producing long-term changes are:

(a) phosphorylation of regulatory proteins (as well as dephosphorylation of others) (see Malmberg, 2000, this volume); (b) positive and negative regulation of gene transcription (see Berthele et al., 2000, this volume); (c) induced synthesis of proteins (as well as reduced synthesis of others); (d) strengthening of some and weakening of other connections (synaptic longterm potentiation, sprouting and pruning) (see Gerber et al., 2000, this volume; Sandkiihler et al., 2000, this volume); and (e) the death or rescuing of neurons. These neuronal changes share initiating events such as glutamate-induced elevations in calcium, maintaining events (nitric oxide synthesis, activation of protein kinases), perpetuating forces (activation of CREB, NP-kB), and terminal results (altered synaptic efficacy). Two critical initiating events in the process of injury-induced synaptic plasticity are an increase in intracellular calcium followed by the activation of calcium-dependent enzymes, including members of the calpain family of neutral proteinases believed to participate in many intracellular processes such as turnover of cytoskeletal proteins, and the regulation of kinase activities and transcription factors. Calpain activation has been linked to the breakdown of microtubule-associated protein (MAP) along with the activation of enzymes triggering programmed cell death (Suzuki et al., 1987). Cytoskeletal proteins, including MAP, are involved in maintaining structural integrity, which is essential for normal cellular function and survival of adult neurons. Degradation of these skeletal elements may contribute to neuronal dysfunction after CNS injury (Siman et al., 1985; Blomgren et al., 1995; Banik et al., 1997). Activation of calpains after CNS injury is therefore thought to be an important factor in determining the extent of cellular dysfunction and likelihood of cell death (Springer et al., 1997; Happel et al., 1981). Consistent with this hypothesis, administration of calpain inhibitors provide significant neuroprotection associated with glutamate excitotoxicity (Caner et al., 1994). These studies underscore the importance of glutamate in excitotoxic neuronal damage and the potential contribution to the establishment of neuronal vulnerability and dysfunction. Evidence supporting the hypothesis that cytoskeletal degradation is extremely sensitive to glutamate- and calcium-mediated excitotoxic events have shown MAP,

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spectrin, and neurofilament proteins undergoing proteolysis after CNS injury involving excitotoxic insult (Banik et al., 1997). Of relevance to the discussion of spinal injury, SC1 results in the rapid degradation of MAP-2 and spectrin (Springer et al., 1997) a process known to be initiated by excessive glutamate receptor activation (Siman et al., 1985). The proposed relationship between degradation of membrane cytoskeletal proteins and central sensitization stems from a body of evidence suggesting that high-frequency afferent stimulation produces postsynaptic changes mediated by glutamate or aspartate (or both). For example, following high-frequency stimulation glutamate binding increases and this correlates with the induction of LTP in hippocampal slice preparations (Lynch and Baudry, 1984). Electron microscopic studies from rats with LTP reveal a rounding of dendritic spines and an increase in the number of synapses (Lee et al., 1980). These changes are not seen in preparations lacking LTP. The relationship between calcium and increased glutamate binding sites follows from the observation that calcium induced a substantial increase in the maximal number, but not the affinity, of glutamate binding in sites in the hippocampus, striatum and cortex (Lynch and Baudry, 1984). Like LTP, ‘kindling’ also produces an increase in glutamate binding sites (Savage et al., 1982). From these results it was concluded that the postsynaptic face of neuronal connections is quite plastic and can be substantially changed by physiological activity. The above studies led to the hypothesis that calcium activates a membrane-associated calpain which breaks up a portion of the cytoskeletal network, producing structural and chemical changes in the region of the postsynaptic membrane (Baudry et al., 1981; Lynch and Baudry, 1984). These events result in previously occluded glutamate receptors being exposed, thereby increasing the size of the postsynaptic response to released transmitter. Continued high bursts of activity or injury increase the availability of glutamate leading to a larger calcium influx and more widespread activation of calcium-dependent proteinases. These events have relevance to the altered functional properties of neurons following SC1 since intracellular calcium and calpain activity increase significantly after SC1 (Li et al., 199.5; Banik et al., 1997).

Other biochemical events potentially contributing to the initiation of injury-induced plasticity include: (a) the calcium activation of phospholipase A2; (b) hydrolysis of phospholipid precursors to arachidonate; and (c) the release of the cis-unsaturated fatty acid oleate which directly stimulates PKC (Linden et al., 1987).PKC activation has recently been shown to evoke mechanical allodynia and thermal hyperalgesia (Palecek et al., 1999) providing further evidence along with that of Malmberg et al. (1997; see Malmberg, 2000, this volume) that PKC is involved in the modulation of nociceptive information in the spinal cord and the onset of neuropathic pain. The production of arachidonic acid potentially exacerbates the injury process by increasing extracellular levels of aspartate and glutamate by inhibiting sodium-dependent uptake (Breukel et al., 1997) and by stimulating exocytosis of glutamate in synergy with PKC activation. Activation of the arachidonic acid cascade also leads to synthesis of eicosanoids which regulate neuronal ion channels and the formation of superoxide free radicals (Piomelli, 1994). In parallel with the above events are changes in the local expression of cytokines, chemokines and adhesion molecules (Hsu et al., 1994). The role of the inflammatory cytokine IL- 1b along with protein synthesis, and activation of NF-kB in synaptic plasticity and chronic pain behaviors in the dynorphin model of neuropathic pain was recently described by Wilcox and colleagues (Laughlin et al., 1999). The increased synthesis and release of inflammatory mediators also triggers the rapid induction of COX-2 and oxygenation of arachidonic acid to prostaglandin endoperoxide H2, which is converted to biologically active end-products by individual synthases or reductases. Simultaneously, since iNOS is coexpressed with COX-2 (Salvemini et al., 1994; Nogawa et al., 1998) and because COX-2 is a heme-containing enzyme, its enzymatic activity is potentiated by nitric oxide (NO), a gas with high affinity for heme iron (Ignarro, 1991). Therefore COX-2 induction could be another mechanism by which NO exerts its pathogenic effects following CNS injury; NO produced by iNOS has been shown to activate COX-2 and increase the output of proinflammatory prostaglandins (Salvemini et al., 1994; see, however, Hoheisel and Mense, 2000, this volume). A final participant in the cellular cascade of synaptic

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plasticity is the high lipid content of CNS membranes, the integrity of which is a prerequisite for normal brain function. The effects of traumatic or ischemic injury leads to oxygen deprivation and compromised lipid metabolism including a decomposition of membrane-bound phospholipids and the release of free fatty acids (Rehncrona et al., 1982). Changes in free fatty acids lead to mitochondrial dysfunction (Lazarewicz et al., 1988), edema (Chan and Fishman, 1978) and production of leukotrienes along the lipoxygenase pathway, some of which are potentially toxic. Conclusions From the above discussion it is clear that there are many possible scenarios by which the biochemical cascade initiated by injury can influence not only the progression of neuronal damage, but also changes in the physiological properties responsible for the response of neurons to peripheral stimuli. The present discussion addressed three important components initiated by injury, each of which potentially contributes to the anatomical and functional plasticity of spinal neurons. Firstly, the influx and/or mobilization of calcium is responsible for the activation of calpain and phospholipase A2. The downstream effects of activating these calcium-dependent enzymes on cytoskeletal proteins, glutamate binding sites, release of glutamate, ion channels, production of free radicals and PKC activation have been associated with events ranging from the strengthening of synaptic efficacy to compromised neuronal function and cell death. Secondly, expression of cytokines, chemokines and adhesion molecules leads to the induction of COX-2 and iNOS and subsequent production of prostanoids and NO, two cellular messengers thought to play an important role in CNS inflammation and sensory processing (Haley and Wilcox, 1992; Meller and Gebhart, 1994). Thirdly, injury-induced release of free fatty acids increases phospholipase A2 activity, compromised mitochondrial function and potential activation of cell death programs. Finally, it is unlikely that any one mechanism discussed in this chapter is solely responsible for the onset of central pain following SCI. Depending on the nature of injury and the progression of

pathological and biochemical changes along the rostrocaudal axis of the cord, it is probable that each of the proposed mechanisms contributes to the onset of this condition. Continued research directed towards specific components of the spinal injury cascade should provide a better understanding of spinal and supraspinal mechanism(s) responsible for this condition and the future development of novel therapeutic strategies. Acknowledgements The author would like to thank the dedicated collaborative assistance of Drs. Shanliang Liu, Kori Brewer, Chen-Guang Yu, Jeffery Plunkett and Laurel Gorman. Expert technical assistance was provided by Gladys Ruenes and Dimarys Sanchez. The work of the author was supported by the Hollfellder Foundation, Paralyzed Veterans of America, Department of Defense, U.S. Army and by funds from the Miami Project and State of Florida Spinal Cord Injury Trust. References Baeuerle, PA. and Baltimore, D. (1991) The physiology of NFkB transcription factor. In: P Cohen and J.G. Foulkes (Eds.), Molecular Aspects of Cellular Regulation-Hormonal Contml of Gene Transcription. Elsevier, Amsterdam, pp. 409432. Banik, N.L., Matzelle, D.C., Wilford, G.G., Osborne, A. and Hogan, L. (1997) Increased calpain content and progressive degradation of nemofilament protein in spinal cord injury. Brain Rex, 752: 301-306. Baudry, M.. Smith, E. and Lynch, G. (1981) Influences of temperature, detergents, and enzymes on glutamate receptor binding and its regulation by calcium in rat hippocampal membranes. Mol. Phamcol., 20: 280-286. Beric, A. (1990) Altered sensation and pain in spinal cord injury. In: M.R. Dimitrijevic, P.D. Wall and U. Lindblom (Eds.), Recent Achievements in Restorative Neurology. Karger, Base], pp. 27-36. Beric, A. (1992) Pain in spinal cord injury. In: L.S. Illis (Ed.), Spinal Cord Dysfunction. Oxford University Press, New York, pp. 156-165. Beric, A., Dimitrijevic, M. and Lindblom, U. (1988) Central dysesthesia syndrome in SC1 patients. Pain, 34: 109-l 16. Berthele, A., Schadrack, J., Castro-Lopes, J.M., Conrad, B., Zieglgansberger, W. and Tolle, T.R. (2000) Neuroplasticity in the spinal cord of monoarthritic rats: from metabolic changes to the detection of interleukin-6 using mRNA differential display. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.),

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