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Spinal cord injury pain: spinal and supraspinal mechanisms.


Sensory abnormalities, including pain, associated with spinal cord injury (SCI) are related to the nature of the lesion, damaged neurological structures, and secondary pathophysiological changes of surviving tissue [1-3]. Although complete loss of sensory and motor functions is thought to most significantly affect individuals with spinal injury, secondary complications that include spasticity, bladder and bowel dysfunctions, infertility, autonomic dysfunction, and pain are among the most difficult consequences to deal with following injury [4]. Over the past 15 years, a systematic examination related to the pathophysiology, clinical characteristics, and treatment of different pain conditions has provided insight into the potential mechanisms contributing to the onset and maintenance of above- and below-level pain associated with SCI [5]. The development of experimental models to study spinal injury combined with clinical studies has provided important information related to spinal and supraspinal changes contributing to the development of at- or below-level pain. At the site of injury, multicomponent excitotoxic and inflammatory cascades affect the survivability and functional state of spinal neurons. Changes in the excitability of neurons secondary to the release of inflammatory mediators along with a decrease in local inhibitory influences and changes in descending modulation provide a permissive environment that leads to the development of spinal pain generators that contribute to the mechanism of injury-induced pain. In this review, I will discuss experimental studies that focus on the spinal and supraspinal mechanisms associated with at- and below-level neuropathic pain. Pain of musculoskeletal, radicular, visceral, or psychogenic origins all are significant in the clinical sequela of spinal injury. These pain syndromes are discussed elsewhere [6-11].


A cascade of cellular, biochemical, and molecular responses to SCI is significant in producing functional changes that contribute to the onset of abnormal sensations, including pain, following spinal injury [2-3,12]. Considering the traumatic and/or ischemic insult associated with injury to the spinal cord parenchyma, one is not surprised that the pathological sequela of injury includes a wide spectrum of events that severely compromise the anatomical and functional integrity of sensory, motor, and autonomic pathways in the spinal cord. Another consideration is the physical factors, including completeness and level of injury, that correlate with pain onset. Unfortunately, few consistent predictors have been identified [1,13], although a positive relationship between the higher incidence of pain in patients with thoracolumbar and incomplete lesions has been described [14]. Several models, including mechanical trauma, isolated lesions, complete transection, chemical lesions, and ischemic injury, each with pathological components found in the human condition, have been used in the study of SCI pain [15-18]. Many of the well-documented changes associated with different SCI models progress in a rostrocaudal direction and influence not only spinal but also cortical and subcortical structures [2]. Given the wide range of pathophysiological changes associated with spinal injury, it is important to identify causal relationships between specific changes and the onset of pain as opposed to merely pointing out events occurring secondary to the injury process. Establishing these causal relationships is critical to identifying underlying mechanisms responsible for pain development.

Selecting effective behavioral measures used to assess mechanical and thermal sensibilities following injury is another challenge in the study of different injury-induced pain conditions. Most behavioral measures used in the study of SCI pain have historically relied on reflex-based responses to peripheral stimuli. Nociceptive reflexes, like tail-flick and hindpaw withdrawal, are regulated by segmentally organized spinal mechanisms and are present in spinalized animals. Lick and guard responses to nociceptive input depend on spino-bulbo-spinal circuits and are present in decerebrate animals [19]. The study of excitability changes of spinal sensory and motor neurons at the level of injury can therefore be evaluated with reflex-based assessment strategies. Unfortunately, enhancement of flexion/withdrawal reflexes (i.e., the spastic syndrome) can be dissociated from the conditions of at- and below-level pain in cases of subtotal SCI [20-21]. The challenge of studying these types of pain, therefore, lies in using appropriate behavioral measures that engage neural substrates responsible for the pain condition being evaluated. If one assumes that below-level pain depends on activation of cortical structures, then to study this type of pain requires behavioral measures that rely on cortical activation. Behavioral outcomes fitting this criterion include operant tasks that rely on cortical involvement for processing sensory information, decisions based on environmental contingencies, and initiation of behavioral responses to nociceptive stimuli [22]. A major misconception in the study of below-level pain is the belief that sensory stimuli delivered to dermatomes below the level of a lesion to evoke reflexive responses qualify as an evaluation of below-level pain. Acceptance of the differences and limitations between responses obtained with operant- versus reflex-based behavioral measures is a major challenge in the study of SCI pain, especially studies related to the evaluation of at- versus below-level pain [22].

In recent years, the systematic study of SCI pain has led to significant advances in understanding specific changes that contribute to developing and maintaining at- and below-level pain. In the following sections, a brief review of some of the more significant contributions is presented.


An important factor in determining potential mechanisms of pain following spinal injury relates to understanding the cascade of pathological, biochemical, and molecular events initiated by ischemic or traumatic insult to the cord. Significant structural damage to the spinal cord parenchyma leads to the reorganization of spinal circuits that integrate, locally process, and transmit sensory information. Ischemic or traumatic insult also changes the expression of chemical mediators that maintain homeostatic balance between inhibitory and excitatory circuits. Equally significant is the disruption of cellular events affecting signaling, transduction, and survival pathways of spinal neurons. Collectively, these events profoundly affect the excitability and functional properties of spinal sensory neurons and ultimately affect evoked and resting sensibilities. Primary and secondary pathophysiological events associated with injury are part of a central injury cascade that initiates pain-related behaviors following injury [12]. Different components of this hypothetical cascade are shown in Figure 1 and include anatomical, neurochemical, excitotoxic, and inflammatory events that have an interdependent relationship and collectively create an environment responsible for changing the functional (physiological) state of spinal sensory neurons leading to the expression of different clinical conditions (e.g., allodynia, hyperalgesia, spontaneous pain). I should mention that it is unlikely that events associated with the onset of SCI pain occur in sequence. Since many contributing factors potentially influence the excitability of central neurons and thus the onset of pain, they most likely do not occur in a programmed sequential fashion. On the contrary, some events associated with the central cascade are more likely occurring simultaneously and the interaction and escalation of events over time create an environment for changes to occur in the functional properties of central neurons, including enhanced responses to peripheral stimuli and/or spontaneous discharges.


Changes in the level of neuronal excitability, denervation supersensitivity, inactivation/activation of cell signaling pathways, and glial-neuronal interactions are all part of the injury cascade that ultimately contributes to the onset of abnormal sensory processing. Since the introduction of the central injury cascade and its role in the initiation of SCI pain, significant progress has been made in understanding many of the individual events associated with each major component. The general construct, however, of interactive injury processes working in concert to produce a permissive environment for functional changes in spinal neurons leading to abnormal clinical/behavioral symptoms remains a viable working model for the onset and maintenance of different injury-induced pain conditions [3,23].

Critical events in the aftermath of SCI include the transient elevation in excitatory amino acids (EAAs) and the production of potentially toxic mediators, e.g., cytokines, reactive oxygen species. EAAs are well-documented to have an important role in neuronal death associated with stroke, hypoxia-ischemia, and traumatic brain injury [24]. Similarly, research supports injury-induced glutamate neurotoxicity in the secondary pathology of ischemic and traumatic spinal injury [25-26]. Using an excitotoxic model of SCI that simulates injury-induced elevations in EAAs, Plunkett et al. found an upregulation of messenger ribonucleic acids (mRNAs) for interleukin (IL)-1[beta], cyclooxygenase-2, nitric oxide synthase (NOS), and death-inducing ligands CD-95 and tumor necrosis factor-[alpha] (TNF-[alpha])-related apoptosis-inducing ligand [27]. Upregulation of mRNA for TNF-[alpha] and dynorphin along with the activation of transcription factors nuclear factor-[kappa]B (NF-[kappa]B) and ELK-1 has also been reported following SCI [28-30]. Activation of the NF-[kappa]B family of transcription factors is significant given its involvement in the inducible regulation of more than 150 genes involved in inflammatory, proliferative, and cell death responses that regulate transcription factors, inflammatory processes, cell survival, and membrane excitability. Importantly, a number of the secondary messengers, receptors, and ionic channels upregulated in response to central nervous system (CNS) injury are important in determining the functional state of spinal sensory neurons. For example, upregulation of sodium channels has been linked to the onset of changes in neuronal excitability and the onset of abnormal sensations following SCI [31].

Other pathological, biochemical, and molecular changes associated with SCI include afferent sprouting in distant segments [32], upregulation of vanilloid receptor expression [33], changes in expression of metabotropic glutamate receptors [34], activation of protein kinases and transcription factors associated with the mitogen-activated protein kinase (MAPK)-signaling pathway [35], increased NR1 serine phosphorylation of the N-methyl-D-aspartate (NMDA) receptor [36], changes in galanin immunoreactivity [37], and increased expression of c-fos mRNA [30,38-39]. Although each of these events is considered part of the central injury cascade, causal relationships with the expression of chronic pain behaviors have not been established.


Over the past 15 years, several mechanisms have been proposed to explain the condition of pain following SCI, including (1) loss of spinal inhibitory mechanisms [17,40], (2) presence of pattern generators within the injured cord [40-42] and supraspinal relay nuclei [43], (3) synaptic plasticity [2], (4) spinal and supraspinal microglia activation [44], and (5) changes in cell-signaling pathways at spinal and supraspinal sites [35,45]. In spite of evidence that cellular or axonal loss following injury predisposes individuals to at- or below-level pain, separating these regionally distinct categories of pain is important (from the standpoint of therapeutic strategies) and considering each as separate, although potentially related conditions. For example, the expression of pain after SCI follows a progressive sequence from at- to below-level pain, suggesting the existence of interactive mechanisms for these two pain conditions [46]. The temporal profile of different pain conditions raises the possibility that abnormal neural activity (spinal and supraspinal) associated with at-level pain may be a predisposing condition in below-level pain development. This relationship might be an important factor in the design of preventive and/or therapeutic strategies.


The dynamic longitudinal progression of tissue damage should be considered in the pathological changes associated with spinal injury. The functional and behavioral significance of this progression is evidenced by the use of neuroprotective agents shown to limit the spread of injury as well as the expression of different pain-related behaviors [47]. These results led to the proposal of a "spatial threshold" in which a critical distance of tissue damage must occur for pain behaviors to develop (Figure 2). This concept evolved from a series of studies in which an approximately 5 mm distance in the dorsal horn gray matter was required for the expression of a spontaneous pain-like behavior (i.e., excessive grooming) [47-49]. From this follows a critical determinant that expression of pain following SCI may include both specific injury-induced anatomical and functional events along with the progressive longitudinal spread of pathophysiological changes within the cord [2,48]. Identifying the mechanisms responsible for the dynamic spread of injury may therefore help researchers develop neuroprotective interventions to use as preventive strategies for different pain conditions.

The spatial threshold hypothesis was tested by Yu et al. using selective neuroprotective agents following SCI [47], including agmatine (NMDA antagonist and NOS inhibitor), IL-10, and cyclosporine A (immunosuppressant). The results of this study showed a delayed onset of spontaneous pain behavior and reduced neuronal loss in the spinal cord of animals treated with neuroprotective agents compared with those treated with saline [47]. Treatment of pain after onset with these same compounds compared with treatment of saline significantly reduced pain behaviors and neuronal loss. These results showed for the first time that administration of neuroprotective agents significantly affected injury-induced spontaneous pain behaviors. Collectively, these results support the conclusions that (1) the expression of pain behaviors depends on a critical distance of neuronal injury along the longitudinal axis of the cord [2,47] and that (2) neuroprotective strategies targeting selected components of the central injury cascade may prevent the progression of pathological conditions that express pain following SCI [2]. Further support for these conclusions is the result of transplant studies in which adrenal chromaffin cells were used to prevent and/or reverse the expression of injury-induced pain behaviors [50-52]. Adrenal chromaffin cells are known to produce several neuroactive substances, including those with neuroprotective properties [53]. The possibility that neuroprotective strategies could conceivably worsen pain by providing an environment for the survival of dysfunctional nociceptive pathways should be considered a caveat of using this strategy of intervention.


One should note that sex, strain, and gonadal hormones also exert significant influences on the onset and progression of spontaneous pain behaviors following SCI [48]. For example, the development of pain-like behaviors following excitotoxic spinal injury in male rats of three different strains and ovariectomized female rats is related to the rostrocaudal spread of a specific pattern of neuronal loss in the dorsal horn [48]. Animals treated with estradiol develop severe pain behaviors, whereas those treated with progesterone have delayed onset and attenuated severity and progression of these behaviors [48]. The fact that sex, strain, and hormonal effects influence the temporal profile of pain behaviors and, more importantly, the longitudinal spread of neuronal damage following injury suggests an additional level of complexity regarding endogenous neuroprotective and neurodegenerative mechanisms in the CNS. Consistent with these observations are other reports describing age, sex, and strain factors contributing to differences in prevalence and severity of pain following SCI [13,54-55]. Unraveling the key components of the complex variables associated with SCI may help researchers develop novel strategies for controlling spinal injury and its clinical consequences.


The initial onset of at-level changes in sensitivity to mechanical and thermal stimuli is believed to reflect, in part, a loss of inhibitory tone within the injured cord [17,56-57]. Loss of inhibition enhances recruitment of surrounding neurons and increases the spread of abnormal at-level sensations, including pain. Coincident with reduced local inhibition is the emergence of a pain-generating mechanism. Evidence supporting this concept led to the proposal that not all postinjury pains are due to noxious input; some may be due to changes in firing patterns, including burst activity and long afterdischarges, of neuronal pools adjacent to an injury site [40]. Evidence consistent with a pain-generating mechanism following injury include (1) the existence of hyperactivity in the spinal cord and thalamus of patients with SCI [43,58-59], (2) effectiveness of local anesthetics in alleviating pain when delivered to the injured cord [41,60], and (3) sensitization and prolonged afterdischarges of spinal sensory neurons following SCI [25,31,42,61-62]. The involvement of this neuronal pain-generating mechanism as a component of the spinal and supraspinal mechanisms of SCI pain is also supported by results of pharmacological studies [63-64]. For example, lidocaine and ketamine, two drugs that reduce membrane excitability and glutamate receptor activation, effectively attenuate SCI pain [65-66]. Efforts to increase inhibition with either baclofen or propofol are also effective [32,67]. The anticonvulsant lamotrigine that blocks sodium channels involved in hyperexcitability is also suggested to be effective in patients with SCI with spontaneous and evoked pain [68] as is the anticonvulsant pregabalin [69].

Importantly, discovering the involvement of spinal lamina I neurons in the pain-generating mechanism was a major step in understanding the mechanism of SCI pain. Evidence for this finding comes from clinical observations showing focal hyperactivity in the superficial dorsal horn of the injured cord [58]. Microcoagulation of these hyperactive areas significantly decreased pain [58,70]. Additional support for the involvement of this region in generating pain was evidence that eliminating neurokinin-1 (NK-1) receptor-expressing neurons in the superficial dorsal horn prevents and/or reverses spontaneous pain behavior after excitotoxic spinal injury [71]. This study provided the first evidence suggesting NK-1 receptor-expressing neurons are a critical component of the spinal mechanism responsible for developing injury-induced at-level pain.

Although significant clinical and preclinical evidence supports the involvement of an abnormal pain generator in SCI pain, support also exists for a role of supraspinal structures, e.g., diencephalon, in this mechanism. The contribution of dysfunctional input from the injured cord along with effects of deafferentation (secondary to the death of spinal projection neurons), sprouting of undamaged fibers, and/or the functional unmasking of nonfunctional local connections could help develop focal generators and/or amplifiers of abnormal discharges in supraspinal structures [3,43,72]. Thus, SCI pain may be expressed when portions of supraspinal targets are deprived of spinal input from at or below the level of injury. Instead, these targets are activated by abnormal (spontaneous or evoked) activity originating from spinal regions above the injury level [3].

Another potential contribution to the pain-generating mechanism is the role of descending bulbospinal monoaminergic pathways. Through a mechanism of descending facilitation, these pathways have been shown to be involved in initiating and maintaining neuropathic pain [73-74]. A role in pain development following SCI is suggested by studies showing anatomical and functional changes in serotonergic (5-hydroxytryptamine [5-HT]) pathways following SCI [75-77]. Further support for these changes come from studies showing facilitation of at-level pain by the 5-HT3 receptor [78] and attenuation of injury-induced pain behaviors and excitability of dorsal horn neurons with spinal transplantation of 5-HT precursor cells [79-80].


Although researchers generally agree that interruption of the spinothalamic tract contributes to SCI pain and specifically to below-level pain, interruption of other pathways and/or abnormal activity in alternative sensory systems may also participate in the expression of below-level pain [72,81]. Below-level pain, for example, may involve lesions of the dorsal columns, because pain associated with syringomyelia is reported to be more prevalent when a central cavity expands to involve dorsal pathways [82]. Similarly, animal models have shown that interruption of the dorsal or dorsolateral columns increases the incidence of overgrooming/autotomy after peripheral nerve injury and that allodynia/hyperalgesia is frequently observed in response to stimulation caudal and ipsilateral to dorsolateral column lesions in monkeys [83]. These results suggest that damage to dorsal spinal pathways may be important in producing SCI below-level neuropathic pain.

Although reduced temperature and pain sensations have been used to support the involvement of damaged spinothalamic connections in developing central pain, recent evidence showed that neuronal hyperexcitability is also important in developing below-level pain. Furthermore, loss of spinothalamic function did not appear to predict this type of pain [84]. This work complements previous magnetic resonance imaging findings showing that patients with below-level pain have larger gray matter lesions than patients without pain [63]. Additional evidence supporting this conclusion comes from studies showing that anterolateral cord lesions result in evoked pain caudal to spinal injury only when gray matter is involved [20] and spontaneous pain behavior can be elicited with spinal lesions restricted to the gray matter [18]. Below-level pain may therefore be expressed when portions of sensory-processing targets are deprived of input from classic pain pathway(s) and are indirectly activated by other sources of alternative input from a dysfunctional neuronal core (i.e., pain-generating mechanism) rostral to the injury site [3].


Another potential mechanism contributing to chronic pain following spinal injury is synaptic plasticity in the brain and spinal cord. An important discovery in the mechanism of acute pain is found in the construct of central sensitization and together with long-term changes in spinal connectivity represents a potential mechanism for persistent pain [85-86]. The changes associated with central sensitization are believed to contribute to alterations in excitability of spinal neurons and ultimately to the development of spinal, and possibly supraspinal, pain generators/amplifiers.

Events involved in producing long-term synaptic changes following injury include (1) phosphorylation of regulatory proteins, (2) positive and negative regulation of gene transcription, (3) injury-induced synthesis of proteins, (4) strengthening and weakening of synaptic connections, and (5) death or rescuing of neurons. The contribution of this hypothetical cascade of biochemical and molecular events to the progression of Alzheimer's, Parkinson's, and cerebrovascular diseases has received much attention in recent years [87-88]. Studies focusing on mechanisms responsible for injury-induced changes similar to those just described may provide new opportunities for therapeutic approaches for managing SCI pain.

Efforts to understand the molecular events associated with spinal injury include a study where components of the MAPK-signaling pathway were evaluated [35]. Following excitotoxic spinal injury, this study showed (1) increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2, (2) increased activation of NF-[kappa]B and phosphorylation of ELK-1, and (3) increased gene expression for the NK-1 receptor and NR1 and NR-2A subunits of the NMDA receptor [35]. Blockade of the MAPK cascade with the MEK inhibitor PD98059 inhibited phosphorylation of ELK-1, activation of NF-[kappa]B, and gene expression of NR1, NR-2A, and NK-1R; and prevented the development of spontaneous pain behavior. Injury-induced elevations in spinal levels of EAAs thus lead to activation of the ERK[right arrow]ELK-1 and NF-[kappa]B signaling cascade and the transcriptional regulation of receptors important to chronic pain development. Blockade of this intracellular cascade prevents the onset of injury-induced spontaneous pain behavior [35].

The results just described support the conclusion that many of the same molecular changes described as activity-dependent following peripheral nerve and tissue injury are also associated with central injury. The expression of these molecular changes suggests that the mechanism responsible for the increased excitability of neurons following spinal injury may be similar to the well-documented activity-dependent mechanism induced by damage to peripheral tissue, a mechanism resulting in activating kinase cascades and ultimately long-term changes in synaptic efficacy and neuronal excitability.

A significant contribution to initiating synaptic plasticity has been attributed to the involvement of glial elements and specifically activation of microglia [89]. In spite of the growing evidence that microglial inhibition reduces pain, prostaglandin E-2 has only recently been shown to be involved in the microglia-to-neuron signaling mechanism to induce dorsal horn sensory neurons to undergo changes in excitability [90]. Furthermore, microglia have also been shown to be activated by CCL21 (chemokine [cc-motif] ligand 21) after SCI [91]. Inhibition of microglial activation after spinal injury reduces pain-related behaviors [44,91], and treatment with minocycline or the Mac-1-SAP immunotoxin reverses morphological changes in microglia and attenuates functional and behavioral consequences of SCI. Therefore, microglia could possibly evolve as a significant therapeutic target in preventing and treating pain associated with spinal injury.


In addition to the well-documented spinal mechanisms of SCI pain, remote effects of injury include increased blood flow in forebrain structures [92], cortical expression of cholecystokinin (CCK) and opioid peptides [93-95], changes in the functional properties of thalamic neurons [31,42,59,96-97], and neuronal death in the cortex [98]. The involvement of these changes in SCI pain development, although not proven, is highly probable. In the study by Morrow et al. [92], significant increases in regional cerebral blood flow were found in the arcuate nucleus, hind limb region of S1 cortex, parietal cortex and thalamic posterior, and ventral posterior medial and lateral nuclei. Changes in somatosensory structures involved in pain processing complement clinical observations showing similar changes in thalamic blood flow following SCI [99], alterations in the chemical profile of ventral posterior lateral (VPL) thalamus in patients with SCI pain [100], and reports of hyperactive foci of thalamic activity in patients with SCI induced spontaneous burning pain [43]. Consistent with these clinical reports are descriptions of VPL neurons showing increased spontaneous activity, enlarged receptive fields, enhanced evoked activity, and the emergence of abnormal burst firing after experimental spinal injury [31].

In addition to these studies, Brewer and colleagues clarified changes in peptidergic transmitter systems at spinal and supraspinal levels following excitotoxic SCI [38,93-95]. Many of these changes mimic what is seen in conditions of neuropathic pain following peripheral nerve injury. Opioid precursors preproenkephalin (PPE) and preprodynorphin (PPD) increased expression in cortical regions associated with nociceptive function: PPE in the anterior cingulate cortex (ACC) and PPD in the parietal cortex. These increases occurred bilaterally following injury, and expression of PPE in the ACC and PPD in the contralateral parietal cortex were significantly higher in animals that developed spontaneous pain behaviors versus those that did not. Receptors for opioid peptides were also differentially expressed in these two groups of animals (pain vs nonpain), with expression levels being affected throughout the medial pain system (i.e., ACC, medial thalamus, periaqueductal gray and rostroventral medulla). In addition to direct effects on opioid peptides and receptors, excitotoxic injury affects the expression of CCK, an endogenous antagonist to opioid analgesia, and several isoforms of protein kinase C, an important enzyme in the phosphorylation of opioid receptors that renders receptors unavailable for binding [101]. These effects of injury were seen throughout the medial pain system and were pronounced in animals with post-SCI pain. Together, these changes create a dysfunctional system within the endogenous pain control system. The importance of these findings is that following SCI, significant changes occur at supraspinal sites involved in pain processing, including changes in several components of the normal pain-modulation system (ligands, receptors, and second messenger for opioids).


Clinical and experimental studies need to identify critical events responsible for the onset of mechanisms of SCI pain. Studies must continue to focus on details of different secondary events associated with the injury process in which dysfunctional spinal and supraspinal neurons emerge. These studies are essential to the design of more effective treatment strategies. Progress in understanding central pain after SCI will require clinically relevant experimental models and behavioral assessment strategies. A single mechanism solely responsible for the onset of central pain following SCI is unlikely. Depending on the nature of injury and the progression of pathological, molecular, and biochemical changes along the rostrocaudal axis of the cord, each of the mechanisms that I have discussed in this review most likely contributes to the onset of SCI pain (Figure 3). Continued basic and clinical research of different aspects of at- and below-level pain should help healthcare professionals better understand spinal and supraspinal mechanisms that cause these conditions.


This material was based on the work of Dr. Yezierski and supported by grant NS40096 from the National Institutes of Health.


The author has declared that no competing interests exist.

Submitted for publication June 16, 2008. Accepted in revised form August 28, 2008.


[1.] Siddall PJ, Taylor DA, McClelland JM, Rutkowski SB, Cousins MJ. Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury. Pain. 1999;81(1-2):187-97. [PMID: 10353507]

[2.] Yezierski RP. Pain following spinal cord injury: Pathophysiology and central mechanisms. In: Sandkuler J, Broom B, Gebhart GF, editors. Nervous system plasticity and chronic pain. Vol 129, Progress in brain research. Amsterdam (the Netherlands): Elsevier Science Pub Co; 2000. p. 429-49. DOI:10.1016/S0079-6123(00)29033-X

[3.] Yezierski RP. Pain following spinal cord injury pain: Central mechanisms. In: Cervero F, Jensen TS, editors. Handbook of clinical neurology. Vol 81, Pain. Amsterdam (the Netherlands): Elsevier Science Pub Co; 2006. p. 293-307.

[4.] Widerstrom-Noga EG, Felipe-Cuevo E, Broton JG, Duncan RC, Yezierski RP. Perceived difficulty in dealing with consequences of spinal cord injury. Arch Phys Med Rehab. 1999;80(5):580-86. [PMID: 10326925] DOI:10.1016/S0003-9993(99)90203-4

[5.] Yezierski, RP, Burchiel, KJ editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002.

[6.] Aim M, Saraste H, Norrbrink C. Shoulder pain in persons with thoracic spinal cord injury: Prevalence and characteristics. J Rehabil Med. 2008;40(4):277-83. [PMID: 18382823] DOI:10.2340/16501977-0173

[7.] Britell CW, Mariano AJ. Chronic pain in spinal cord injury. Phys Med Rehabil. 1991;5:71-82.

[8.] Samuelsson KA, Tropp H, Gerdle B. Shoulder pain and its consequences in paraplegic spinal-cord injured, wheelchair users. Spinal Cord. 2004;42(1):41-46. [PMID: 14713943] DOI:10.1038/

[9.] Summers JD, Rapoff MA, Varghese G, Porter K, Palmer RE. Psychosocial factors in chronic spinal cord injury pain. Pain. 1991;47(2):183-89. [PMID: 1762813] DOI:10.1016/0304-3959(91)90203-A

[10.] Tunks E. Pain in spinal cord injured patients. In: Bloch RF, Basbaum M, editors. Management of spinal cord injuries. Baltimore (MD): William and Wilkins; 1986. p. 180-211.

[11.] Ullrich PM. Pain following spinal cord injury. Phys Med Rehabil Clin N Am. 2007;18(2):217-33. [PMID: 17543770] DOI:10.1016/j.pmr.2007.03.001

[12.] Yezierski RP. Pathophysiology and animal models of spinal cord injury pain. In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 117-36.

[13.] Werhagen L, Budh CN, Hutling C, Molander C. Neuropathic pain after traumatic spinal cord injury--Relations to gender, spinal level, completeness, and age at the time of injury. Spinal Cord. 2004;42(12):665-73. [PMID: 15289801] DOI:10.1038/

[14.] Demirel G, Yllmas H, Gencosmanoglu B, Kesiktas N. Pain following spinal cord injury. Spinal Cord. 1998;36(1):25-28. [PMID: 9471134] DOI:10.1038/

[15.] Christensen MD, Everhart AW, Pickeman J, Hulsebosch CE. Mechanical and thermal allodynia in chronic central pain following spinal cord injury. Pain. 1996;68(1):97-107. [PMID: 9252004] DOI:10.1016/S0304-3959(96)03224-1 JRRD, Volume 46, Number 1, 2009

[16.] Siddall P, Xu CL, Cousins M. Allodynia following traumatic spinal cord injury in the rat. Neuroreport. 1995;6(9): 1241-44. [PMID: 7669978] DOI:10.1097/00001756-199506090-00003

[17.] Wiesenfeld-Hallin Z, Hao JX, Aldskogius H, Seiger A, Xu XJ. Allodynia-like symptoms in rats after spinal cord ischemia: An animal model of central pain. In: Boivie J, Hansson P, Lindblom U, editors. Touch, temperature, and pain in health and disease: Mechanisms and assessments. Vol 4, Progress in pain research and management. Seattle (WA): IASP Press; 1994. p. 455-72.

[18.] Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL. Excitotoxic spinal cord injury: Behavioral and morphological characteristics of a central pain model. Pain. 1998;75(1):141-55. [PMID: 9539683] DOI:10.1016/S0304-3959(97)00216-9

[19.] Woolf CJ. Long term alterations in the excitability of the flexion reflex produced by peripheral tissue injury in the chronic decerebrate rat. Pain. 1984;18(4):325-43. [PMID: 6728499] DOI:10.1016/0304-3959(84)90045-9

[20.] Vierck CJ, Light AR. Assessment of pain sensitivity in dermatomes caudal to spinal cord injury in rats. In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 137-54.

[21.] Vierck CJ, Cannon RL, Stevens KA, Acosta-Rua AJ, Wirth ED. Mechanisms of increased pain sensitivity within dermatomes remote from an injured segment of the spinal cord. In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 155-73.

[22.] Vierck CJ, Hansson PT, Yezierski RP. Clinical and pre-clinical pain assessment: Are we measuring the same thing? Pain. 2008;135(1):7-10. DOI:10.1016/j.pain.2007.12.008

[23.] Yezierski RP. Pain following spinal cord injury: The clinical problem and experimental studies. Pain. 1996;68(2-3): 185-94. [PMID: 9121805] DOI:10.1016/S0304-3959(96)03178-8

[24.] Regan R, Choi DW. Excitoxicity and central nervous system trauma. In: Salzman SK, Faden AL, editors. The neurobiology of central nervous system trauma. New York (NY): Oxford Press; 1994. p. 173-81.

[25.] Hao JX, Xu XJ, Yu YX, Seiger A, Wiesenfeld-Hallin Z. Transient spinal cord ischemia induces temporary hypersensitivity of dorsal horn wide dynamic range neurons to myelinated, but not unmyelinated, fiber input. J Neurophysiol. 1992;68(2):384-91. [PMID: 1527565]

[26.] Yezierski RP, Santana M, Park DH, Madsen PW. Neuronal degeneration and spinal cavitation following intraspinal injections of quisqualic acid in the rat. J Neurotrauma. 1993; 10(4):445-56. [PMID: 8145267]

[27.] Plunkett JA, Yu CG, Easton JM, Bethea JR, Yezierski RP. Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat. Exp Neurol. 2001;168(1):144-54. [PMID: 11170729] DOI:10.1006/exnr.2000.7604

[28.] Bethea JR, Castro M, Keane RW, Lee TT, Dietrich WD, Yezierski RP. Traumatic spinal cord injury induces nuclear factor kappa B activation. J Neurosci. 1998;18(9):3251-60. [PMID: 9547234]

[29.] Hayashi M, Ueyama T, Nemoto K, Tamaki T, Senba E. Sequential mRNA expression for immediate early genes, cytokines, and neurotrophins in spinal cord injury. J Neurotrauma. 2000;17(3):203-18. [PMID: 10757326] DOI:10.1089/neu.2000.17.203

[30.] Yakovlev AG, Faden AI. Sequential expression of c-fos proto-oncogene, TNF-alpha, and dynorphin genes in spinal cord following experimental traumatic injury. Mol Chem Neuropathol. 1994;24(2-3):179-90. [PMID: 7702707] DOI:10.1007/BF02815410

[31.] Hains BC, Waxman SG. Sodium channel expression and the molecular pathophysiology of pain after SCI. Prog Brain Res. 2007;161:195-203. [PMID: 17618978] DOI:10.1016/S0079-6123(06)61013-3

[32.] Herman RM, D'Luzansky SC, Ippoliti R. Intrathecal baclofen suppresses central pain in patients with spinal lesions: A pilot study. Clin J Pain. 1992;8(4):338-45. [PMID: 1493344] DOI:10.1097/00002508-199212000-00008

[33.] Zhou Y, Wang Y, Abdelhady M, Mourad MS, Hassouna MM. Change of vanilloid receptor 1 following neuromodulation in rats with spinal cord injury. J Surg Res. 2002; 107(1):140-44. [PMID: 12384077]

[34.] Mills CD, Fullwood SD, Hulsebosch CE. Changes in metabotropic glutamate receptor expression following spinal cord injury. Exp Neurol. 2001;170(2):244-57. [PMID: 11476590] DOI:10.1006/exnr.2001.7721

[35.] Yu CG, Yezierski RP. Activation of the ERJ 1/2 signaling cascade by excitotoxic spinal cord injury. Mol Brain Res. 2005;138(2):244-55. DOI:10.1016/j.molbrainres.2005.04.013

[36.] Caudle RM, Perez FM, King C, Yu CG, Yezierski RP. N-methyl-D-aspartate receptor subunit expression and phosphorylation following excitotoxic spinal cord injury in rats. Neurosci Lett. 2003;349(1):37-40. [PMID: 12946581] DOI:10.1016/S0304-3940(03)00700-6

[37.] Zvarova K, Murray E, Vizzard MA. Changes in galanin immunoreactivity in rat lumbosacral spinal cord and dorsal root ganglia after spinal cord injury. J Comp Neurol. 2004; 475(4):590-603. [PMID: 15236239] DOI:10.1002/cne.20195

[38.] Abraham KE, Brewer KL. Expression of c-fos mRNA is increased and related to dynorphin mRNA expression following excitotoxic spinal cord injury in the rat. Neurosci Lett. 2001;307(3):187-91. [PMID: 11438395] DOI:10.1016/S0304-3940(01)01955-3

[39.] Siddall PJ, Xu CL, Floyd N, Keay KA. C-fos expression in the spinal cord in rats exhibiting allodynia following contusive spinal cord injury. Brain Res. 1999;851(1-2):281-86. [PMID: 10642858] DOI:10.1016/S0006-8993(99)02173-3

[40.] Melzack R, Loeser JD. Phantom body pain in paraplegics: Evidence for a central "pattern generating mechanism" for pain. Pain. 1978;4(3):195-210. [PMID: 273200] DOI:10.1016/0304-3959(77)90133-6

[41.] Pollock LJ, Brown M, Boshes B, Finkelman I, Chor H, Arieff AJ, Finkel JR. Pain below the level of injury of the spinal cord. AMA Arch Neurol Psychiatry. 1951;65(3): 319-22. [PMID: 273200]

[42.] Yezierski RP, Park SH. The mechanosensitivity of spinal sensory neurons following intraspinal injections of quisqualic acid in the rat. Neurosci Lett. 1993;157(1):115-19. [PMID: 8233021] DOI:10.1016/0304-3940(93)90656-6

[43.] Ohara S, Garonzik I, Hua S, Lenz FA. Microelectrode studies of the thalamus in patients with central pain and in control patients with movement disorders. In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 219-36.

[44.] Hains BC, Waxman SG. Activated microglia contribute to the maintenance of chronic pain after spinal cord injury. J Neurosci. 2006;26(16):4308-17. [PMID: 16624951] DOI:10.1523/JNEUROSCI.0003-06.2006

[45.] Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE. Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp Neurol. 2006;199(2):397-407. [PMID: 16478624] DOI:10.1016/j.expneurol.2006.01.003

[46.] Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ. A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain. 2003;103(3):249-57. DOI:10.1016/S0304-3959(02)00452-9

[47.] Yu CG, Fairbanks CA, Wilcox GL, Yezierski RP. Effects of agmatine, interleukin-10, and cyclosporin on spontaneous pain behavior after excitotoxic spinal cord injury in rats. J Pain. 2003;4(3):129-40. DOI:10.1054/jpai.2003.11

[48.] Gorman AL, Yu CG, Ruenes GR, Daniels L, Yezierski RP. Conditions affecting the onset, severity, and progression of a spontaneous pain-like behavior after excitotoxic spinal cord injury. J Pain. 2001;2(4):229-40. [PMID: 14622821] DOI:10.1054/jpai.2001.22788

[49.] Fairbanks CA, Schreiber KL, Brewer KL, Yu CG, Stone LS, Kitto KF, Nguyen HO, Grocholski BM, Shoeman DW, Kehl LJ, Regunathan S, Reis DJ, Yezierski RP, Wilcox GL. Agmatine reverses pain induced by inflammation, neuropathy, and spinal cord injury. Proc Natl Acad Sci U S A. 2000;97(19):10584-89. [PMID: 10984543] DOI:10.1073/pnas.97.19.10584

[50.] Brewer KL, Yezierski RP. Effects of adrenal medullary transplants on pain-related behaviors following excitotoxic spinal cord injury. Brain Res. 1998:798(1-2):83-92. [PMID: 9666085] DOI:10.1016/S0006-8993(98)00398-9

[51.] Hains BC, Chastain KM, Everhart AW, McAdoo DJ, Hulsebosch CE. Transplants of adrenal medullary chromaffin cells reduce forelimb and hindlimb allodynia in a rodent model of chronic central pain after spinal cord hemisection injury. Exp Neurol. 2000:164(2):426-37. [PMID: 10915581] DOI:10.1006/exnr.2000.7439

[52.] Yu W, Hao JX, Xu XJ, Saydoff J, Haegerstrand A, Hokfelt T, Wiesenfeld-Hallin Z. Long-term alleviation of allodynia-like behaviors by intrathecal implantation of bovine chromaffin cells in rats with spinal cord injury. Pain. 1998: 74(2-3):115-22. [PMID: 9520225] DOI:10.1016/S0304-3959(97)00204-2

[53.] Sagen J. Long-term alleviation of allodynia-like Transplants of adrenal update. In: Lanza, RP, Chick WL, editors. Yearbook of cell and tissue transplantation. The Hague (the Netherlands): Kluwer Academic; 1996. p. 71-89.

[54.] Mills CD, Hains BC, Johnson KM, Hulsebosch CE. Strain and model differences in behavioral outcomes after spinal cord injury in rat. J Neurotrauma. 2001;18(8):743-56. [PMID: 11526981] DOI:10.1089/089771501316919111

[55.] McColl MA, Charlifue S, Glass C, Lawson N, Savic G. Aging, gender, and spinal cord injury. Arch Phys Med Rehabil. 2004;85(3):363-67. [PMID: 15031818] DOI:10.1016/j.apmr.2003.06.022

[56.] Hao JX, Xu XJ, Yu YX, Seiger A, Wiesenfeld-Hallin Z. Baclofen reverses the hypersensitivity of dorsal horn wide dynamic range neurons to mechanical stimulation after transient spinal cord ischemia; implications for a tonic GABAergic inhibitory control of myelinated fiber input. J Neurophysiol. 1992;68(2):392-96. [PMID: 1527566]

[57.] Zhang AL, Hao JX, Seiger A, Xu XJ, Wiesenfeld-Hallin Z, Grant G, Aldskogius H. Decreased GABA immunoreactivity in spinal cord dorsal horn neurons after transient spinal cord ischemia in the rat. Brain Res. 1994;656(1): 187-90. [PMID: 7804836] DOI:10.1016/0006-8993(94)91383-8

[58.] Edgar RE, Best LG, Quail PA, Obert AD. Computer-assisted DREZ microcoagulation: Posttraumatic spinal deafferentation pain. J Spinal Disord. 1993;6(1):48-56. [PMID: 8439716]

[59.] Hains BC, Saab CY, Waxman SG. Alterations in burst firing of thalamic VPL neurons and reversal by Nav1.3 antisense after spinal cord injury. J Neurophysiol. 2006;95(6): 3343-52. [PMID: 16481457] DOI:10.1152/jn.01009.2005

[60.] Loubser PG, Donovan WH. Diagnostic spinal anesthesia in chronic spinal cord injury pain. Paraplegia. 1991;29(1): 25-36. [PMID: 1708859]

[61.] Drew GM, Siddall PJ, Duggan AW. Responses of spinal neurones to cutaneous and dorsal root stimuli in rats with mechanical allodynia after contusive spinal cord injury. Brain Res. 2001;893(1-2):59-69. [PMID: 11222993] DOI:10.1016/S0006-8993(00)03288-1

[62.] Hoheisel U, Scheifer C, Trudrung P, Unger T, Mense S. Pathophysiological activity in rat dorsal horn neurones in segments rostral to a chronic spinal cord injury. Brain Res. 2003;974(1-2):134-45. [PMID: 12742631] DOI:10.1016/S0006-8993(03)02571-X

[63.] Finnerup NB, Gyldensted C, Nielsen E, Kristensen AD, Back FW, Jensen TS. MRI in chronic spinal cord injury patients with and without central pain. Neurology. 2003; 61(11):1569-75. [PMID: 14663044]

[64.] Xu XJ, Hao JX, Wiesenfeld-Hallin Z. Physiological and pharmacological characterization of a rat model of spinal cord injury pain after spinal ischemia. In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 175-87.

[65.] Attal N, Gaude V, Brasseur L, Dupuy M, Guirimand F, Parker F, Bouhassira D. Intravenous lidocaine in central pain: A double-blind, placebo-controlled, psychophysical study. Neurology. 2000;54(3):564-74. [PMID: 10680784]

[66.] Eide PK, Stubhaug A, Stenehjem AE. Central dysesthesia pain after traumatic spinal cord injury is dependent on N-methyl-D-aspartate receptor activation. Neurosurgery. 1995; 37(6):1080-87. [PMID: 8584148] DOI:10.1097/00006123-199512000-00007

[67.] Canavero S, Bonicalzi V, Pagni CA, Castellano G, Merante R, Gentile S, Bradac GB, Bergui M, Benna P, Vighetti S, Moia MC. Propofol analgesia in central pain: Preliminary clinical observations. J Neurol. 1995;242(9): 561-67. [PMID: 8551317] DOI:10.1007/BF00868808

[68.] Finnerup NB, Johannesen IL, Sindrup SH, Bach FW, Jensen TS. Pharmacological treatment of spinal cord injury pain. In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 341-51.

[69.] Siddall PJ, Cousins MJ, Otte A, Griesing T, Chambers R, Murphy TK. Pregabalin in central neuropathic pain associated with spinal cord injury: A placebo-controlled trial. Neurology. 2006;67:1792-1800.

[70.] Falci S, Best L, Bayles R, Lammertse D, Starnes C. Dorsal root entry zone microcoagulation for spinal cord injury-related central pain: Operative intramedullary electrophysiological guidance and clinical outcome. J Neurosurg. 2002; 97(2 Suppl):193-200. [PMID: 12296678]

[71.] Yezierski RP, Yu CG, Mantyh PW, Vierck CJ, Lappi DA. Spinal neurons involved in the generation of at-level pain following spinal injury in the rat. Neurosci Lett. 2004; 361(1-3):232-36. [PMID: 15135936] DOI:10.1016/j.neulet.2003.12.035

[72.] Vierck CJ, Siddall PJ, Yezierski RP. Pain following spinal cord injury: Animal models and mechanistic studies. Pain. 2000;89(1):1-5. [PMID: 11113287] DOI:10.1016/S0304-3959(00)00463-2

[73.] Ossipov MH, Lai J, Malan TP, Porreca F. Spinal and supraspinal mechanisms of neuropathic pain. Ann N Y Acad Sci. 2000;909:12-24. [PMID: 10911921]

[74.] Porreca F, Ossipov MH, Gebhart GF. Chronic pain and medullary descending facilitation. Trends Neurosci. 2002; 25(6):319-25. [PMID: 12086751] DOI:10.1016/S0166-2236(02)02157-4

[75.] Hains BC, Everhart AW, Fullwood SD, Hulsebosch CE. Changes in serotonin, serotonin transporter expression and serotonin denervation supersensitivity: Involvement in chronic central pain after spinal hemisection in the rat. Exp Neurol. 2002;175(2):347-62. [PMID: 12061865] DOI:10.1006/exnr.2002.7892

[76.] Kalous A, Osborne PB, Keast JR. Acute and chronic changes in dorsal horn innervation by primary afferents and descending supraspinal pathways after spinal cord injury. J Comp Neurol. 2007;504(3):238-53. [PMID: 17640046] DOI:10.1002/cne.21412

[77.] Bruce JC, Oatway MA, Weaver LC. Chronic pain after clip-compression injury of the rat spinal cord. Exp Neurol. 2002;178:33-48. [PMID: 12460606] DOI:10.1006/exnr.2002.8026

[78.] Oatway MA, Chen Y, Weaver LC. The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury. Pain. 2004;110(1-2):259-68. [PMID: 15275776] DOI:10.1016/j.pain.2004.03.040

[79.] Hains BC, Johnson KM, McAdoo DJ, Eaton MJ, Hulsebosch CE. Engraftment of serotonergic precursors enhances locomotor function and attenuates chronic central pain behavior following spinal hemisection injury in the rat. Exp Neurol. 2001;171(2):361-78. [PMID: 11573989] DOI:10.1006/exnr.2001.7751

[80.] Hains BC, Johnson KM, Eaton MJ, Willis WD, Hulsebosch CE. Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat. Neuroscience. 2003;116(4):1097-1110. [PMID: 12617951] DOI:10.1016/S0306-4522(02)00729-7

[81.] Johnson RD, Hubscher CH. Plasticity in supraspinal viscerosomatic convergent neurons following chronic spinal cord injury. In: Yezierski RP, Burchiel K, editors. Spinal cord injury pain: Assessment, mechanisms, management. Vol 23, Progress in pain research and management. Seattle (WA): IASP Press; 2002. p. 205-17. YEZIERSKI. Spinal cord injury pain

[82.] Milhorat TH, Kotzen RM, Mu HT, Capocelli AL Jr, Milhorat RH. Dysesthetic pain in patients with syringomyelia. Neurosurgery. 1996;38(5):940-47. [PMID: 8727819] DOI:10.1097/00006123-199605000-00017

[83.] Vierck CJ Jr, Light AR. Allodynia and hyperalgesia within dermatomes caudal to a spinal cord injury in primates and rodents. In: Sandkuler J, Broom B, Gebhart GF, editors. Nervous system plasticity and chronic pain. Vol 129, Progress in brain research. Amsterdam (the Netherlands): Elsevier Science Pub Co; 2000. p. 411-28. DOI:10.1016/S0079-6123(00)29032-8

[84.] Finnerup NB, Sorensen L, Biering-Sorensen F, Johannesen IL, Jensen TS. Segmental hypersensitivity and spinothalamic function in spinal cord injury. Exp Neurol. 2007; 207(1):139-49. [PMID: 17628539] DOI:10.1016/j.expneurol.2007.06.001

[85.] Ji RR, Woolf CJ. Neuronal plasticity and signal transduction in nociceptive neurons: Implications for the initiation and maintenance of pathological pain. Neurobiol Dis. 2001;8(1): 1-10. [PMID: 11162235] DOI:10.1006/nbdi.2000.0360

[86.] Woolf CJ, Csotigan M. Transcriptional and posttranslational plasticity and the generation of inflammatory pain. Proc Natl Acad Sci U S A. 1999;96(14):7723-30. [PMID: 10393888] DOI:10.1073/pnas.96.14.7723

[87.] Irvine GB, El-Agnaf OM, Shankar GM, Walsh DM. Protein aggregation in the brain: The molecular basis for Alzheimer's and Parkinson's diseases. Mol Med. 2008; 14(7-8):451-64. [PMID: 18368143]

[88.] Youdim MB, Grunblatt E, Levites Y, Maor G, Mandel S. Early and late molecular events in neurodegeneration and neuroprotection in Parkinson's disease MPTP model as assessed by cDNA microarray; the role of iron. Neurotox Res. 2002;4(7-8):679-89. DOI:10.1080/1029842021000045507

[89.] McMahon SB, Cafferty WB, Marchand F. Immune and glial cell factors as pain mediators and modulators. Exp Neurol. 2005;192(2):444-62. [PMID: 15755561] DOI:10.1016/j.expneurol.2004.11.001

[90.] Zhao P, Waxman SG, Hains BC. Extracellular signal-regulated kinase-regulated microglia-neuron signaling by prostaglandin E2 contributes to pain after spinal cord injury. J Neurosci. 2007;27(9):2357-68. [PMID: 17329433] DOI:10.1523/JNEUROSCI.0138-07.2007

[91.] Zhao P, Waxman SG, Hains BC. Modulation of thalamic nociceptive processing after spinal cord injury through remote activation of thalamic microglia by cysteine-cysteine chemokine ligand 21. J Neurosci. 2007;27(33):8893-8902. [PMID: 17699671] DOI:10.1523/JNEUROSCI.2209-07.2007

[92.] Morrow TJ, Paulson PE, Brewer KL, Yezierski RP, Casey KL. Chronic, selective forebrain responses to excitotoxic dorsal horn injury. Exp Neurol. 2000;161(1):220-26. [PMID: 10683288] DOI:10.1006/exnr.1999.7246

[93.] Abraham KE, McGinty JF, Brewer KL. Spinal and supraspinal changes in opioid mRNA expression are related to the onset of pain behaviors following excitotoxic spinal cord injury. Pain. 2001;90(1-2):181-90. [PMID: 11166985] DOI:10.1016/S0304-3959(00)00402-4

[94.] Brewer KL, McMillan D, Nolan T, Shum K. Cortical changes in cholecystokinin mRNA are related to spontaneous pain behaviors following excitotoxic spinal cord injury in the rat. Brain Res Mol Brain Res. 2003;118(1-2):171-74. [PMID: 14559369] DOI:10.1016/j.molbrainres.2003.08.006

[95.] Nolan T, Brewer KL. Supraspinal expression of endogenous opioid ligands and opioid receptors after excitotoxic spinal cord injury. Soc Neurosci. 2005;436:17.

[96.] Gerke MB, Duggan AW, Xu L, Siddall PJ. Thalamic neuronal activity in rats with mechanical allodynia following contusive spinal cord injury. Neuroscience. 2003;117(3): 715-22. [PMID: 12617975] DOI:10.1016/S0306-4522(02)00961-2

[97.] Hubscher CH, Johnson RD. Chronic spinal cord injury induced changes in the responses of thalamic neurons. Exp Neurol. 2006;197(1):177-88. [PMID: 16266704] DOI:10.1016/j.expneurol.2005.09.007

[98.] Lee BH, Lee KH, Kim UJ, Yoon DH, Sohn JH, Choi SS, Yi IG, Park YG. Injury in the spinal cord may produce cell death in the brain. Brain Res. 2004;1020(1-2):37-44. [PMID: 15312785] DOI:10.1016/j.brainres.2004.05.113

[99.] Ness TJ, San Pedro EC, Richards JS, Kezar L, Liu H-G, Mountz JM. A case of spinal cord injury-related pain with baseline rCBF brain SPECT imaging and beneficial response to gabapentin. Pain. 1998;78(2):139-43. [PMID: 9839825] DOI:10.1016/S0304-3959(98)00153-5

[100.] Pattany PM, Yezierski RP, Widerstrom-Noga EG, Bowen BC, Martinez-Arizala A, Garcia BR, Quencer RM. Proton magnetic resonance spectroscopy of the thalamus in patients with chronic neuropathic pain after spinal cord injury. AJNR Am J Neuroradiology. 2002;23(6):901-5. [PMID: 12063213]

[101.] Nolan T, Brewer KL. Spinal and supraspinal expression of PKC isoforms following excitotoxic spinal cord injury and implications for chronic pain management. J Pain. 2005;6(3 Suppl 1):S10. DOI:10.1016/j.jpain.2005.01.037

Abbreviations: 5-HT = 5-hydroxytryptamine, ACC = anterior cingulate cortex, CCK = cholecystokinin, CNS = central nervous system, EAA = excitatory amino acid, ERK = extracellular signal-regulated kinase, IL = interleukin, MAPK = mitogen-activated protein kinase, mRNA = messenger ribonucleic acid, NF-[kappa]B = nuclear factor-[kappa]B, NK-1 = neurokinin-1, NMDA = N-methyl-D-aspartate, NOS = nitric oxide synthase, PPD = preprodynorphin, PPE = preproenkephalin, SCI = spinal cord injury, TNF-[alpha] = tumor necrosis factor-[alpha], VPL = ventral posterior lateral (ventroposterolateral).

Robert P. Yezierski, PhD

Department of Orthodontics and the Comprehensive Center for Pain Research, University of Florida, Gainesville, FL

Address all correspondence to Robert P. Yezierski, PhD; Department of Orthodontics, 1600 SW Archer Road, PO Box 100444, University of Florida, Gainesville, FL 32610; 352-392-4081; fax: 352-392-3031. Email:

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Author:Yezierski, Robert P.
Publication:Journal of Rehabilitation Research & Development
Article Type:Report
Date:Jan 1, 2009
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