Segmental hypersensitivity and spinothalamic function in spinal cord injury pain

The mechanisms underlying central pain following spinal cord injury (SCI) are unsettled. The purpose of the present study was to examine differences in spinothalamic tract function below injury level and evoked pain in incomplete SCI patients with neuropathic pain below injury level (central pain) versus those without such pain. A clinical examination, quantitative sensory testing and magnetic resonance imaging (MRI) were performed in 10 SCI patients with below-level pain and in 11 SCI patients without neuropathic pain. Patients with and without pain had similar reductions of mechanical and thermal detection thresholds below injury level. SCI patients with central pain had sensory hypersensitivity in dermatomes corresponding to the lesion level more frequently than SCI patients without pain, but this may in part be explained by the exclusion of at-level spontaneous pain in the pain-free group. The rostral-caudal extent of the lesion measured by MRI did not differ between the two patient groups, and there were no statistically significant differences in any of the predefined areas of interest on the axial plane images. This study suggests that neuronal hyperexcitability plays a key role in central SCI pain and furthermore - in contrast to previous findings - that loss of spinothalamic functions does not appear to be a predictor for central neuropathic pain in spinal cord injury.     

Sensory perception in complete spinal cord injury

OBJECTIVES: To describe sensations evoked by painful or repetitive stimulation below injury level in patients with a clinically complete (American Spinal Injury Association, ASIA Grade A) spinal cord injury (SCI). MATERIAL AND METHODS: Twenty-four patients (11 with central neuropathic pain and 13 without pain) with a traumatic SCI above the tenth thoracic vertebra were examined using quantitative sensory testing, MR imaging, and somatosensory evoked potentials (SEP). RESULTS: Painful (pressure, pinch, heat or cold) or repetitive (pinprick) stimuli elicited vague localized sensations in 12 patients (50%). Pain, spasticity, and spasms were equally seen in SCI patients with or without localized sensations. SEP and MRI did not differentiate between these two groups. CONCLUSION: The present study suggests retained sensory communication across the injury in complete SCI, i.e. 'sensory discomplete' SCI.     

Gliopathy ensures persistent inflammation and chronic pain after spinal cord injury

Research focused on improving recovery of function, including the reduction of central neuropathic pain (CNP) after spinal cord injury (SCI) is essential. After SCI, regional neuropathic pain syndromes above, at and below the level or spinal injury develop and are thought to have different mechanisms, but may share common dysfunctional glial mechanisms. Detloff et al., [Detloff, M.R., Fisher, L.C., McGaughy, V., Longbrake, E.E., Popovich, P.G., Basso, D.M., Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats. Exp. Neurol. (2008), doi: 10.1016/j.expneurol.2008.04.009.] describe events in the lumbar region of the spinal cord after a midthoracic SCI injury, the so called “below-level” pain and compares the findings to peripheral nerve lesion findings. This commentary briefly reviews glial contributions and intracellular signaling mechanisms, both neuronal and glial, that provide the substrate for CNP after SCI, including the persistent glial production of factors that can maintain sensitization of dorsal horn neurons in segments remote from the spinal injury; ie. dorsal horn hyperexcitability to formerly non noxious stimuli that become noxious after SCI resulting in allodynia. The term “gliopathy” is proposed to describe the dysfunctional and maladaptive response of glial cells, specifically astrocytes and microglia, to neural injury that is initiated by the sudden injury induced increase in extracellular concentrations of glutamate and concomitant production of several proinflammatory molecules. It is important to understand the roles that different glia play in “gliopathy”, a condition that appears to persist after SCI. Furthermore, targeted treatment of gliopathy will attenuate mechanical allodynia in both central and peripheral neuropathic pain syndromes.     

Remote activation of microglia and pro-inflammatory cytokines predict the onset and severity of below-level neuropathic pain after spinal cord injury in rats

Spinal cord injury (SCI) impairs sensory systems causing chronic allodynia. Mechanisms underlying neuropathic pain have been more extensively studied following peripheral nerve injury (PNI) than after central trauma. Microglial activation, pro-inflammatory cytokine production and activation of p38 MAP kinase pathways may induce at-level allodynia following PNI. We investigated whether midthoracic SCI elicits similar behavioral and cellular responses below the level of injury (lumbar spinal cord; L5). Importantly, we show that anatomical connections between L5 and supraspinal centers remain intact after moderate SCI allowing direct comparison to a well-established model of peripheral nerve injury. We found that SCI elicits below-level allodynia of similar magnitude to at-level pain caused by a peripheral nerve injury. Moreover, the presence of robust microglial activation in L5 cord predicted allodynia in 86% of rats. Also increased phosphorylation of p38 MAP kinase occurred in the L5 dorsal horn of allodynic rats. For below-level allodynia after SCI, TNF-α and IL-1β increased in the L5 dorsal horn by 7 dpo and returned to baseline by 35 dpo. Interestingly, IL-6 remains at normal levels early after SCI and increases at chronic time points. Increased levels of pro-inflammatory cytokines also occurred in the thalamus after SCI-induced allodynia. These data suggest that remote microglial activation is pivotal in the development and maintenance of below-level allodynia after SCI. Fractalkine, a known activator of microglia, and astrocytes were not primary modulators of below-level pain. Although the mechanisms of remote microglial activation are unknown, this response may be a viable target for limiting or preventing neuropathic pain after SCI in humans.     

New evidence for preserved somatosensory pathways in complete spinal cord injury: A fMRI study

Trauma to the spinal cord rarely results in complete division of the cord with surviving nerves sometimes remaining silent or failing to function normally. The term motor or sensory discomplete has been used to describe this important but unclassified subgroup of complete SCI. Importantly, silent motor or sensory pathways may contribute to aversive symptoms (spasticity, pain) or improved treatment success. To demonstrate more objectively the presence of subclinical preserved somatosensory pathways in clinically complete SCI, a cross‐sectional study using functional MRI (fMRI) was undertaken. The presence of brain activation following innocuous brushing of an insensate region below‐injury (great toe) was analyzed in 23 people (19 males (83%), mean ± SD age 43 ± 13 years) with clinically complete (AIS A) SCI with (n = 13) and without (n = 10) below‐level neuropathic pain and 21 people without SCI or pain (15 males (71%); mean ± SD age 41 ± 14 years). Location appropriate, significant fMRI brain activation was detected in 48% (n = 11/23) of subjects with clinically complete SCI from below‐injury stimulation. No association was found between the presence of subclinical sensory pathways transmitting innocuous mechanical stimuli (dorsal column medical lemniscal) and below‐level neuropathic pain (χ² = 0.034, P = 0.9). The high prevalence of sensory discomplete injuries (～50% complete SCI) strengthens the case to explore inclusion of this category into the international SCI taxonomy (ISNCSCI). This would ensure more widespread inclusion of discomplete SCI in ongoing pain and motor recovery research. Neurophysiological tests such as fMRI may play a role in this process. Hum Brain Mapp 39:588–598, 2018. © 2017 Wiley Periodicals, Inc.     

Spinal cord injury pain – mechanisms and treatment

In spinal cord injury (SCI), pain is a major cause of disability. A review of experimental and human studies, which provide insight into the mechanisms and treatment of SCI neuropathic pain are presented. Each of a series of pathophysiologic changes after SCI may be relevant for the development of SCI neuropathic pain. These changes are discussed in relation to neuropathic pain at and below the level of SCI. SCI neuropathic pain is difficult to treat. Experimental and human randomized, double-blind, placebo-controlled, clinical trials on pharmacologic treatment of SCI pain are summarized.     

Fire and phantoms after spinal cord injury: Na+ channels and central pain

Neuropathic pain and phantom phenomena occur commonly after spinal cord injury (SCI) but their molecular basis is not yet fully understood. Recent findings demonstrate abnormal expression of the Nav1.3 Na(+) channel within second-order spinal cord dorsal horn neurons and third-order thalamic neurons along the pain pathway after SCI, and suggest that this change makes these neurons hyperexcitable so that they act as pain amplifiers and generators. Delineation of molecular changes that contribute to hyperexcitability of pain-signaling neurons might lead to identification of molecular targets that will be useful in the treatment of neuropathic pain after SCI and related nervous system injuries.     

Spinal cord injury, dendritic spine remodeling, and spinal memory mechanisms

Spinal cord injury (SCI) often results in the development of neuropathic pain, which can persist for months and years after injury. Although many aberrant changes to sensory processing contribute to the development of chronic pain, emerging evidence demonstrates that mechanisms similar to those underlying classical learning and memory can contribute to central sensitization, a phenomenon of amplified responsiveness to stimuli in nociceptive dorsal horn neurons. Notably, dendritic spines have emerged as major players in learning and memory, providing a structural substrate for how the nervous system modifies connections to form and store information. Until now, most information regarding dendritic spines has been obtained from studies in the brain. Recent experimental data in the spinal cord, however, demonstrate that Rac1-regulated dendritic spine remodeling occurs on second-order wide dynamic range neurons and accompanies neuropathic pain after SCI. Thus, SCI-induced synaptic potentiation engages a putative spinal memory mechanism. A compelling, novel possibility for pain research is that a synaptic model of long-term memory storage could explain the persistent nature of neuropathic pain. Such a conceptual bridge between pain and memory could guide the development of more effective strategies for treatment of chronic pain after injury to the nervous system.     

Neuropathic Pain After Spinal Cord Injury: Challenges and Research Perspectives

Neuropathic pain is a debilitating consequence of spinal cord injury (SCI) that remains difficult to treat because underlying mechanisms are not yet fully understood. In part, this is due to limitations of evaluating neuropathic pain in animal models in general, and SCI rodents in particular. Though pain in patients is primarily spontaneous, with relatively few patients experiencing evoked pains, animal models of SCI pain have primarily relied upon evoked withdrawals. Greater use of operant tasks for evaluation of the affective dimension of pain in rodents is needed, but these tests have their own limitations such that additional studies of the relationship between evoked withdrawals and operant outcomes are recommended. In preclinical SCI models, enhanced reflex withdrawal or pain responses can arise from pathological changes that occur at any point along the sensory neuraxis. Use of quantitative sensory testing for identification of optimal treatment approach may yield improved identification of treatment options and clinical trial design. Additionally, a better understanding of the differences between mechanisms contributing to at- versus below-level neuropathic pain and neuropathic pain versus spasticity may shed insights into novel treatment options. Finally, the role of patient characteristics such as age and sex in pathogenesis of neuropathic SCI pain remains to be addressed.     

Pathophysiological activity in rat dorsal horn neurones in segments rostral to a chronic spinal cord injury

As a sequel of complete spinal cord injury (SCI), patients often develop chronic pain which is perceived at or just below the level of the lesion. Likewise, in animal models of SCI, spontaneous and evoked pain-related behaviour can be observed. In the present study, the hypothesis was tested that pain related behaviour after SCI in animals is at least partly due to neuronal hyperactivity in spinal segments rostral to the site of injury. In rats with a chronic transected spinal cord, the impulse activity of single dorsal horn neurones was recorded in two locations: (1) directly rostrally adjacent to the lesion, and (2) 2-3 segments more rostrally. Cord transections were made either at the thoracic or at the lumbar level. Sham-operated rats and rats which underwent no surgical interventions served as controls. Compared with both controls, in SCI animals the background activity of the neurones had a significantly higher level in both series. Often the activity showed a pathophysiological altered discharge pattern. Following SCI, there was a general increase in the mechanical responsiveness of neurones that were recorded 2-3 segments rostrally to the lesion. The results suggest that neuronal hyperactivity in spinal segments just rostral to the lesion may contribute to chronic spontaneous SCI pain. Further, there is some indication that the allodynia perceived in body regions near and above the level of the SCI may be due to increased responsiveness to weak stimuli of neurones located more rostrally to the lesion.     

An IL-1 receptor antagonist blocks a morphine-induced attenuation of locomotor recovery after spinal cord injury

Morphine is one of the most commonly prescribed medications for the treatment of chronic pain after a spinal cord injury (SCI). Despite widespread use, however, little is known about the secondary consequences of morphine use after SCI. Unfortunately, our previous studies show that administration of a single dose of morphine, in the acute phase of a moderate spinal contusion injury, significantly attenuates locomotor function, reduces weight gain, and produces symptoms of paradoxical pain (Hook et al., 2009). The current study focused on the cellular mechanisms that mediate these effects. Based on data from other models, we hypothesized that pro-inflammatory cytokines might play a role in the morphine-induced attenuation of function. Experiment 1 confirmed that systemic morphine (20 mg/kg) administered one day after a contusion injury significantly increased expression levels of spinal IL-1β 24 h later. Experiment 2 extended these findings, demonstrating that a single dose of morphine (90 μg, i.t.) applied directly onto the spinal cord increased expression levels of spinal IL-1β at both 30 min and 24 h after administration. Experiment 3 showed that administration of an interleukin-1 receptor antagonist (IL-1ra, i.t.) prior to intrathecal morphine (90 μg), blocked the adverse effects of morphine on locomotor recovery. Further, pre-treatment with 3 μg IL-1ra prevented the increased expression of at-level neuropathic pain symptoms that was observed 28 days later in the group treated with morphine-alone. However, the IL-1ra also had adverse effects that were independent of morphine. Treatment with the IL-1ra alone undermined recovery of locomotor function, potentiated weight loss and significantly increased tissue loss at the injury site. Overall, these data suggest that morphine disrupts a critical balance in concentrations of pro-inflammatory cytokines in the spinal cord, and this undermines recovery of function.     

Blockade of the 5-HT3 receptor for days causes sustained relief from mechanical allodynia following spinal cord injury

Chronic neuropathic pain is a frequent, serious outcome of spinal cord injury (SCI) that is highly refractory to treatment. Serotonin can contribute to neuropathic pain after SCI, as suggested by our previous observation that transient blockade of the 5-HT(3) receptor by intrathecal injections of the antagonist ondansetron reduces mechanical allodynia after SCI in rats. The current study determined whether intrathecal or intravenous infusion of ondansetron for 3 or 7 days, respectively, could cause sustained blockade of mechanical allodynia at and below the level of a twelfth thoracic clip compression injury in rats. Intrathecal 3-day infusion of ondansetron (2.0 microg/hr), targeted to the cord rostral to the SCI and commencing at 28 days after SCI, decreased at-level mechanical allodynia by 40% and below-level allodynia by 60% compared with saline-treated rats (controls). This reduction was sustained throughout drug delivery and for 1 day afterward. During the next 3 days, allodynia gradually returned toward the values of saline-treated rats. An initial experiment showed that bolus intravenous injections of ondansetron (20-100 microg) at 28 days after SCI decreased both at- and below-level allodynia for 90-120 min. Intravenous 7-day infusions (20 microg/hr), commencing at 28 days after SCI, significantly decreased at-level allodynia by 48% and below-level allodynia by 51% compared with controls. This reduction of allodynia lasted throughout the infusion and for 1-3 days afterward while pain responses gradually approached those of controls. These findings suggest a potential role of 5-HT(3) receptor antagonism in the relief of neuropathic pain after SCI in humans.     

Intrathecal injection of carbenoxolone, a gap junction decoupler, attenuates the induction of below-level neuropathic pain after spinal cord injury in rats

The most common type of chronic pain following spinal cord injury (SCI) is central neuropathic pain and SCI patients typically experience mechanical allodynia and thermal hyperalgesia. The present study was designed to examine the potential role of astrocyte gap junction connectivity in the induction and maintenance of “below-level” neuropathic pain in SCI rats. We examined the effect of intrathecal treatment with carbenoxolone (CARB), a gap junction decoupler, on SCI-induced bilateral thermal hyperalgesia and mechanical allodynia during the induction phase (postoperative days 0 to 5) and the maintenance phase (days 15 to 20) following T13 spinal cord hemisection. Immunohistochemistry was performed to determine potential SCI-induced changes in spinal astrocyte activation and phosphorylation of the NMDA receptor NR1 subunit (pNR1). CARB administered during the induction period dose-dependently attenuated the development of bilateral thermal hyperalgesia and mechanical allodynia. Intrathecal CARB also significantly reduced the bilateral SCI-induced increase in GFAP-immunoreactive (ir) staining and the number of pNR1-ir cell profiles in the spinal cord dorsal horn compared to vehicle-treated rats. In contrast, CARB treatment during the maintenance phase had no effect on the established thermal hyperalgesia and mechanical allodynia nor on spinal GFAP expression or the number of pNR1-ir cell profiles. These results indicate that gap junctions play a critical role in the activation of astrocytes distant from the site of SCI and in the subsequent phosphorylation of NMDA receptors in the lumbar spinal cord. Both of these processes appear to contribute to the induction of bilateral below-level pain in SCI rats.     

Bladder activation by selective stimulation of pudendal nerve afferents in the cat

Bladder contractions evoked by pudendal nerve stimulation in both spinal intact and spinal transected cats support the possibility of restoring urinary function in persons with chronic spinal cord injury (SCI). However, electrically evoked bladder responses in persons with SCI were limited to transient contractions at relatively low pressures. This prompted the present study, which presents a detailed quantification of the responses evoked by selective stimulation of individual branches of the pudendal nerve at different stimulation frequencies. In spinal intact cats anesthetized with α-chloralose, selective frequency-dependent electrical activation of the sensory (2 Hz ≤ f ≤ 50 Hz), cranial sensory (f ≤ 5 Hz), dorsal genital (f ≥ 20 Hz) and rectal perineal (f ≤ 10 Hz) branches of the pudendal nerve evoked sustained bladder contractions dependent on the stimulation frequency. Contractions evoked by selective electrical stimulation resulted in significant increases in voiding efficiency compared to bladder emptying by distension-evoked contractions (p_ANOVA < 0.05). Acute spinal transection abolished reflex bladder contractions evoked by low frequency stimulation of the cranial sensory or rectal perineal branches, whereas contractions evoked by high frequency stimulation of the dorsal genital branch remained intact. This study presents evidence for two distinct micturition pathways (spino-bulbo-spinal vs. spinal reflexes) activated by selective afferent pudendal nerve stimulation, the latter of which may be applied to restore bladder function in persons with SCI.     

Chronic spinal cord injury induced changes in the responses of thalamic neurons

Sensory disturbances following spinal cord injury (SCI) include chronic pain, which is often localized at spinal levels just rostral to the lesion (referred to as at-level neuropathic pain) and not effectively relieved by traditional treatments. In the present study, a clinically relevant spinal contusion injury was made at the spinal T8 level in 11 deeply anesthetized male rats. Behavioral testing just prior to terminal electrophysiological experiments (done at 30 days post-injury) demonstrated at-level sensitivity to touching the trunk (i.e., allodynia) in 64% of the animals. Electrophysiological data (urethane anesthesia) were obtained for 218 single somatovisceral convergent neurons that were located throughout 12 subregions of the thalamus. In total, 90% (197 of 218) responded to noxious at-level pinch, compared to 52% for pinching the dorsal trunk at the same level in uninjured controls (our previously published data--recorded from 133 total neurons). In addition, 33% of the total neurons tested also responded to gentle touch (dorsal trunk) versus 9% in controls. A comparison of electrophysiological and behavioral data for each individual animal reveals novel tactile neuronal responses within ventral and posterior thalamic subnuclei for those rats showing signs of at-level allodynia. These data suggest that neurons in specific regions of thalamus undergo significant changes in responsiveness following severe chronic SCI. The observed plasticity and ensuing hypersensitivity are likely part of the central reorganization producing the multitude of sensory disturbances that surface following SCI.     

Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats

In the spinal cord, neuron and glial cells actively interact and contribute to neurofunction. Surprisingly, both cell types have similar receptors, transporters and ion channels and also produce similar neurotransmitters and cytokines. The neuroanatomical and neurochemical similarities work synergistically to maintain physiological homeostasis in the normal spinal cord. However, in trauma or disease states, spinal glia become activated, dorsal horn neurons become hyperexcitable contributing to sensitized neuronal-glial circuits. The maladaptive spinal circuits directly affect synaptic excitability, including activation of intracellular downstream cascades that result in enhanced evoked and spontaneous activity in dorsal horn neurons with the result that abnormal pain syndromes develop. Recent literature reported that spinal cord injury produces glial activation in the dorsal horn; however, the majority of glial activation studies after SCI have focused on transient and/or acute time points, from a few hours to 1 month, and peri-lesion sites, a few millimeters rostral and caudal to the lesion site. In addition, thoracic spinal cord injury produces activation of astrocytes and microglia that contributes to dorsal horn neuronal hyperexcitability and central neuropathic pain in above-level, at-level and below-level segments remote from the lesion in the spinal cord. The cellular and molecular events of glial activation are not simple events, rather they are the consequence of a combination of several neurochemical and neurophysiological changes following SCI. The ionic imbalances, neuroinflammation and alterations of cell cycle proteins after SCI are predominant components for neuroanatomical and neurochemical changes that result in glial activation. More importantly, SCI induced release of glutamate, proinflammatory cytokines, ATP, reactive oxygen species (ROS) and neurotrophic factors trigger activation of postsynaptic neuron and glial cells via their own receptors and channels that, in turn, contribute to neuronal-neuronal and neuronal-glial interaction as well as microglia-astrocytic interactions. However, a systematic review of temporal and spatial glial activation following SCI has not been done. In this review, we describe time and regional dependence of glial activation and describe activation mechanisms in various SCI models in rats. These data are placed in the broader context of glial activation mechanisms and chronic pain states. Our work in the context of work by others in SCI models demonstrates that dysfunctional glia, a condition called "gliopathy", is a key contributor in the underlying cellular mechanisms contributing to neuropathic pain.     

C-fos expression in the spinal cord of rats exhibiting allodynia following contusive spinal cord injury

Contusive spinal cord injury (SCI) may result in central neuropathic pain marked by allodynia-like features in the dermatomes close to the level of injury. The aim of this study was to compare the laminar distribution of activated neurons (as determined by c-fos immediate early gene expression) in the spinal cord immediately above the level of a SCI in rats with or without allodynia-like features. Non-noxious mechanical stimulation was applied to half the animals in the dermatomes corresponding to the level of injury prior to perfusion. Stimulation resulted in a significant increase in c-fos labelling in all laminae of the spinal dorsal horn in the segment immediately above the level of injury only in allodynic animals. Animals that had allodynia also demonstrated a significant increase in the level of c-fos labelling in lamina III, IV and V of the dorsal horn without stimulation. Thus, allodynia following SCI is associated with significant increases in basal and evoked c-fos expression (“neuronal activity”) in response to non-noxious mechanical stimulation. The data also suggest that allodynia-like behaviour following SCI cannot be accounted for solely by changes occurring at a spinal level.     

Preserved somatosensory conduction in complete spinal cord injury: Discomplete SCI

ObjectiveSpinal cord injury (SCI) disrupts the communication between brain and body parts innervated from below-injury spinal segments, but rarely results in complete anatomical transection of the spinal cord. The aim of this study was to investigate residual somatosensory conduction in clinically complete SCI, to corroborate the concept of sensory discomplete SCI.MethodsWe used fMRI with a somatosensory protocol in which blinded and randomized tactile and nociceptive stimulation was applied on both legs (below-injury level) and one arm (above-injury level) in eleven participants with chronic complete SCI. The experimental design accounts for possible confounding mechanical (e.g. vibration) and cortico-cortical top-down mechanisms (e.g. attention/expectation).ResultsSomatosensory stimulation on below-level insensate body regions activated the somatotopically corresponding part of the contralateral primary somatosensory cortex in six out of eleven participants.ConclusionsOur results represent afferent-driven cortical activation through preserved somatosensory connections to the brain in a subgroup of participants with clinically complete SCI, i.e. sensory discomplete SCI.SignificanceIdentifying patients with residual somatosensory connections might open the door for new rehabilitative and restorative strategies as well as inform research on SCI-related conditions such as neuropathic pain and spasticity.     

Ionotropic glutamate receptors contribute to maintained neuronal hyperexcitability following spinal cord injury in rats

In this study, we examined whether topical treatment of glutamate receptor antagonists attenuate hyperexcitability of lumbar spinal dorsal horn neurons following low thoracic hemisection spinal cord injury in rats. Four weeks after spinal hemisection, neuronal activity in response to mechanical stimuli applied on the peripheral receptive field was significantly increased in three different phenotypes of lumbar spinal dorsal horn neurons: wide dynamic range (WDR), low threshold (LT) and high threshold (HT). Topical application of MK-801 (NMDA receptor antagonist, 50 µg) significantly attenuated the activity of WDR, but not LT and HT neurons; whereas, NBQX (AMPA receptor antagonist, 0.5 and 1 µg) significantly attenuated neuronal activity in all three phenotypes of neurons (*p < 0.05). However, MCPG (group I/II metabotropic glutamate receptor antagonist, 100 µg) had no effect. The present study, in the context of previous work, suggests that ionotropic glutamate receptor activation play critical roles in the maintenance of neuronal hyperexcitability and neuropathic “below-level” pain behavior following spinal hemisection injury.