Effect of NMDA NR2B antagonist on neuropathic pain in two spinal cord injury models

N-Methyl-d-aspartate (NMDA) receptors are thought to play an important role in the processes of central sensitization and pathogenesis of neuropathic pain, particularly after spinal cord injury (SCI). NMDA antagonists effectively reduce neuropathic pain, but serious side effects prevent their use as therapeutic drugs. NMDA NR2B antagonists have been reported to effectively reduce inflammatory and neuropathic pain. In this study, we investigated the effects of NR2B antagonists on neuropathic pain and the expression of NR2B in the spinal cord in 2 SCI models. SCI was induced at T12 by a New York University impactor (contusion) or by sectioning of the lateral half of the spinal cord (hemisection). Ifenprodil (100, 200, 500, 1000nmol) and Ro25-6981 (20, 50, 100, 200nmol) were intrathecally injected and behavioral tests were conducted. Ifenprodil increased the paw withdrawal threshold in both models but also produced mild motor depression at higher doses. Ro25-6981 increased the mechanical nociceptive threshold in a dose-dependent manner without motor depression. NR2B expression was significantly increased on both sides at the spinal segments of L1-2 and L4-5 in the hemisection model but did not change in the contusion model. Increased expression of NR2B in the hemisection model was reduced by intrathecal ifenprodil. These results suggest that intrathecal NMDA NR2B antagonist increased the mechanical nociceptive threshold after SCI without motor depression. A selective subtype of NMDA receptor, such as NR2B, may be a more selective target for pain control because NMDA receptors play a crucial role in the development and maintenance of chronic pain.     

Brain circuitry underlying pain in response to imagined movement in people with spinal cord injury

Pain following injury to the nervous system is characterized by changes in sensory processing including pain. Although there are many studies describing pain evoked by peripheral stimulation, we have recently reported that pain can be evoked in subjects with complete spinal cord injury (SCI) during a motor imagery task. In this study, we have used functional magnetic resonance imaging to explore brain sites underlying the expression of this phenomenon. In 9 out of 11 subjects with complete thoracic SCI and below-level neuropathic pain, imagined foot movements either evoked pain in a previously non-painful region or evoked a significant increase in pain within the region of on-going pain (3.2 ± 0.7–5.2 ± 0.8). In both controls (n = 19) and SCI subjects, movement imagery evoked signal increases in the supplementary motor area and cerebellar cortex. In SCI subjects, movement imagery also evoked increases in the left primary motor cortex (MI) and the right superior cerebellar cortex. In addition, in the SCI subjects, the magnitude of activation in the perigenual anterior cingulate cortex and right dorsolateral prefrontal cortex was significantly correlated with absolute increases in pain intensity. These regions expanded to include right and left anterior insula, supplementary motor area and right premotor cortex when percentage change in pain intensity was examined. This study demonstrates that in SCI subjects with neuropathic pain, a cognitive task is able to activate brain circuits involved in pain processing independently of peripheral inputs.     

Calcium channel alpha-2-delta-1 protein upregulation in dorsal spinal cord mediates spinal cord injury-induced neuropathic pain states

Spinal cord injury (SCI) commonly results in the development of neuropathic pain, which can dramatically impair the quality of life for SCI patients. SCI-induced neuropathic pain can be manifested as both tactile allodynia (a painful sensation to a non-noxious stimulus) and hyperalgesia (an enhanced sensation to a painful stimulus). The mechanisms underlying these pain states are poorly understood. Clinical studies have shown that gabapentin, a drug that binds to the voltage-gated calcium channel alpha-2-delta-1 subunit (Ca_vα2δ-1) proteins is effective in the management of SCI-induced neuropathic pain. Accordingly, we hypothesized that tactile allodynia post SCI is mediated by an upregulation of Ca_vα2δ-1 in dorsal spinal cord. To test this hypothesis, we examined whether SCI-induced dysregulation of spinal Ca_vα2δ-1 plays a contributory role in below-level allodynia development in a rat spinal T9 contusion injury model. We found that Ca_vα2δ-1 expression levels were significantly increased in L4-6 dorsal, but not ventral, spinal cord of SCI rats that correlated with tactile allodynia development in the hind paw plantar surface. Furthermore, both intrathecal gabapentin treatment and blocking SCI-induced Ca_vα2δ-1 protein upregulation by intrathecal Ca_vα2δ-1 antisense oligodeoxynucleotides could reverse tactile allodynia in SCI rats. These findings support that SCI-induced Ca_vα2δ-1 upregulation in spinal dorsal horn is a key component in mediating below-level neuropathic pain states, and selectively targeting this pathway may provide effective pain relief for SCI patients.     

Above-level mechanical hyperalgesia in rats develops after incomplete spinal cord injury but not after cord transection, and is reversed by amitriptyline, morphine and gabapentin

Spinal cord injury (SCI) is a major cause of persistent neuropathic pain of central origin. Recent evidence suggests neuropathic pain in clinically complete SCI patients correlates with limited sensory function below the lesion (sensory discomplete). On this basis we examined if the onset of mechanical hyperalgesia was different in rodents after a severe incomplete clip-compression SCI versus a complete spinal cord transection at thoracic segment T13. Above-level withdrawal behaviors evoked by forepaw stimulation provided evidence of mechanical hyperalgesia after incomplete but not complete SCI, whereas below-level responses evoked by hindpaw stimulation revealed hypersensitivity after both injuries. The latency of the above-level response was 4-5 wks but was longer after a moderate clip-compression injury. Mechanical hyperalgesia was fully reversed by three analgesic drugs used in treating neuropathic SCI pain, but their duration of action differed significantly, showing a rank order of amitriptyline (24-48 h) ? morphine (6 h) > gabapentin (2 h). Evidence of central sensitization in cervical spinal cord segments that receive sensory projections from the forelimbs was provided by immunohistochemistry for Zif268, a functional marker of neuroplasticity. Zif268-immunoreactive neurons in laminae I/II increased in response to repetitive noxious forepaw stimulation in the incomplete SCI group, and this response was reduced in the complete transection and sham-operated groups. These data are consistent with the hypothesis that neuropathic pain of cord origin is more likely to develop after SCI when there is an incomplete loss of axons traversing the lesion.     

Effects of Etanercept and Minocycline in a rat model of spinal cord injury

Loss of function is usually considered the major consequence of spinal cord injury (SCI). However, pain severely compromises the quality of life in nearly 70% of SCI patients. The principal aim of this study was to assess the contribution of Tumor necrosis factor α (TNF‐α) to SCI pain. TNF‐α blockers have already been successfully used to treat inflammatory disorders but there are few studies on its effect on neuropathic pain, especially following SCI. Following T13 spinal cord hemisection, we examined the effects on mechanical allodynia and microglial activation of immediate and delayed chronic intrathecal treatment with etanercept, a fusion protein blocker of TNF‐α. Immediate treatment (starting at the time of injury) with etanercept resulted in markedly reduced mechanical allodynia 1, 2, 3 and 4 weeks after SCI. Delayed treatment had no effect. Immediate etanercept treatment also reduced spinal microglial activation assessed by OX‐42 immunostaining, a putative marker of activated microglia. To assess whether the effects of etanercept were mediated via decreased microglial activation, we examined the effects of the microglial inhibitor, minocycline which significantly reduced the development of pain behaviours at 1 and 2 weeks after SCI compared to saline treatment. Minocycline also significantly reduced microglial OX‐42 expression. Furthermore, minocycline decreased the expression of noxious‐stimulation‐induced c‐Fos, suggesting an effect on evoked neuronal activity. This study demonstrates that TNF‐α plays an important role in the establishment of neuropathic pain following SCI, seemingly dependent on microglial activation. Pharmacological targeting of TNF‐α may offer therapeutic opportunities for treating SCI pain.     

Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain.

Neuropathic pain after spinal cord injury (SCI) represents a difficult problem that is commonly refractory to conventional medical management. To determine if spinal release of gamma-amino butyric acid (GABA) could reduce below-level central neuropathic pain after SCI, we constructed a replication-incompetent herpes simplex virus (HSV)-based vector encoding one isoform of human glutamic acid decarboxylase (GAD67). Dorsal root ganglion (DRG) neurons transduced in vitro or in vivo by subcutaneous inoculation produced GAD and released GABA constitutively. T13 spinal cord hemisection resulted in central neuropathic pain manifested by mechanical allodynia and thermal hyperalgesia. Subcutaneous inoculation of the vector into both feet reduced both manifestations of below-level SCI pain; the vector-mediated effect was partially reversed by intrathecal bicuculline or phaclofen at doses that did not affect thresholds in normal or injured uninoculated animals. Vector-mediated GABA release attenuated the increase in spinal calcitonin gene-related peptide immunoreactivity caused by cord hemisection. These results suggest that HSV-mediated gene transfer to DRG could be used to treat below-level central neuropathic pain after incomplete SCI.     

嗅鞘细胞移植治疗脊髓损伤后顽固性神经性疼痛17例报道

目的探讨嗅鞘细胞移植对脊髓损伤后顽固性神经性疼痛的治疗效果。方法对细胞学治疗后获得疗效的脊髓损伤合并顽固性神经性疼痛患者的临床资料进行总结。2004年11月～2007年11月间的17例患者,其中男性15例,女性2例,年龄18～68岁,平均40.4岁。受伤6～312个月,平均105.9个月,受伤原因包括车祸、坠落、放射性损伤、机器挤压伤、枪伤、跳水。疼痛持续时间6～309个月,平均102.2个月。嗅球嗅鞘细胞胰蛋白酶消化成单细胞后培养12～14 d。细胞移植到损伤段的上下两端。疼痛评价使用国际神经修复学会脊髓损伤日常生活功能评价量表：0分为极度疼痛,止痛药无效;1分为中度疼痛,需用强效止痛药;2分为轻度疼痛,普通止痛药有效;3分为无疼痛。结果随访时间0.5～88个月,平均17.5个月,疼痛平均改善1.2分。结论嗅鞘细胞移植对脊髓损伤后神经性疼痛有一定治疗作用。     

Characterization of Hyperacute Neuropathic Pain after Spinal Cord Injury: A Prospective Study

There is currently a lack of information regarding neuropathic pain in the very early stages of spinal cord injury (SCI). In the present study, neuropathic pain was assessed using the Douleur Neuropathique 4 Questions (DN4) for the patient's worst pain within the first 5 days of injury (i.e., hyperacute) and on follow-up at 3, 6, and 12 months. Within the hyperacute time frame (i.e., 5 days), at- and below-level neuropathic pain were reported as the worst pain in 23% (n = 18) and 5% (n = 4) of individuals with SCI, respectively. Compared to the neuropathic pain observed in this hyperacute setting, late presenting neuropathic pain was characterized by more intense painful electrical and cold sensations, but less itching sensations. Phenotypic differences between acute and late neuropathic pain support the incorporation of timing into a mechanism-based classification of neuropathic pain after SCI. The diagnosis of acute neuropathic pain after SCI is challenged by the presence of nociceptive and neuropathic pains, with the former potentially masking the latter. This may lead to an underestimation of the incidence of neuropathic pain during the very early, hyperacute time points post-injury.Trial registrationClinicalTrials.gov (Identifier: NCT01279811)PerspectiveThis article presents distinct pain phenotypes of hyperacute and late presenting neuropathic pain after spinal cord injury and highlights the challenges of pain assessments in the acute phase after injury. This information may be relevant to clinical trial design and broaden our understanding of neuropathic pain mechanisms after spinal cord injury.     

Effect of Repetitive Transcranial Magnetic Stimulation Over the Hand Motor Cortical Area on Central Pain After Spinal Cord Injury

Kang BS, Shin HI, Bang MS. Effect of repetitive transcranial magnetic stimulation over the hand motor cortical area on central pain after spinal cord injury.

Objective

To evaluate the analgesic effect of repetitive transcranial magnetic stimulation (rTMS) applied on the hand motor cortical area in patients with spinal cord injury (SCI) who have chronic neuropathic pain at multiple sites in the body, including the lower limbs, trunk, and pelvis.

Design

Blinded, randomized crossover study.

Setting

University hospital outpatient setting.

Participants

Patients (N=13) with motor complete or incomplete SCI and chronic central pain (11 completed the study).

Interventions

rTMS was applied on the hand motor cortical area using a figure-of-eight coil. One thousand stimuli were applied daily on 5 consecutive days. Real and sham rTMS were separated by 12 weeks.

Main Outcome Measures

Numeric rating scale (NRS) for average and worst pain and the Brief Pain Inventory (BPI).

Results

At 1 week after the end of the rTMS period, the average NRS scores changed from 6.45±2.25 to 5.45±1.81 with real stimulation and from 6.18±1.83 to 5.91±2.07 with sham stimulation, and did not differ between treatments. The interference items of the BPI also did not differ between the real and sham rTMS. The effect of time on the NRS score for worst pain was significant with real stimulation but not with sham stimulation.

Conclusions

The therapeutic efficacy of rTMS was not demonstrated when rTMS was applied to the hand motor cortical area in patients with chronic neuropathic pain at multiple sites in the body, including the lower limbs, trunk, and pelvis. However, the results for worst pain reduction suggest that further studies are required in which rTMS is applied with a more intensive stimulation protocol.     

Oral administration of the p38α MAPK inhibitor,UR13870, inhibits affective pain behavior after spinal cord injury

The p38α mitogenous activated protein kinase (MAPK) cell signaling pathway is a key mechanism of microglia activation and has been studied as a target for neuropathic pain. The effect of UR13870, a p38α MAPK inhibitor, on microglia expression in the anterior cingulate cortex (ACC) and spinal dorsal horn was addressed after T9 contusion spinal cord injury (SCI) in the rat, in addition to behavioral testing of pain-related aversion and anxiety. Administration of intravenous UR13870 (1 mg/kg i.v.) and pregabalin (30 mg/kg i.v.) reduced place escape avoidance paradigm (PEAP) but did not affect open-field anxiety behavior 42 days after SCI. PEAP behavior was also reduced in animals administered daily with oral UR13870 (10 mg/kg p.o.) and preserved spinal tissue 28 days after SCI. Although UR13870 (10 mg/kg p.o.) failed to reduce OX-42 and glial fibrillar acid protein immunoreactivity within the spinal dorsal horn, a reduction toward the control level was observed close to the SCI site. In the anterior cingulate cortex (ACC), a significant increase in OX-42 immunoreactivity was identified after SCI. UR13870 (10 mg/kg p.o.) treatment significantly reduced OX-42, metabotropic glutamate type 5 receptor (mGluR5), and NMDA (N-methyl-d-aspartate) 2B subunit receptor (NR2B) expression in the ACC after SCI. To conclude, oral treatment with a p38α MAPK inhibitor reduces the affective behavioral component of pain after SCI in association with a reduction of microglia and specific glutamate receptors within the ACC. Nevertheless the role of neuroinflammatory processes within the vicinity of the SCI site in the development of affective neuropathic pain cannot be excluded.     

Motor-evoked potentials reflect spinal cord function in post-traumatic syringomyelia

The purpose of this study was to examine electrophysiologic abnormalities, including motor-evoked potentials, in a patient with post-traumatic syringomyelia before and after syringopleural shunting. A patient with C5 quadriplegia presented with pain, ascending sensory loss, and new weakness in the left upper extremity two yr after spinal cord injury. MRI revealed a syrinx extending from C2 to T12. We measured central motor conduction times (CMCTs) to the biceps, median F-wave latencies, needle electromyography and motor nerve conduction studies. Six days before surgery, CMCTs were 9.0 ms on the left and 7.8 ms on the right (normal less than 8.0), median F-waves were absent on the left and needle EMG revealed evidence of denervation in the left biceps. Fifteen days after syringopleural shunting at the T7 level, CMCTs had dropped to 6.9 ms on the left and 4.6 ms on the right; the left median F-wave reappeared with a normal latency. Repeat MRI revealed the syrinx to be smaller in diameter. These results suggest that CMCTs measured from magnetic stimulation of the motor cortex may be useful in the diagnosis of post-traumatic syringomyelia, as well as for following such patients postoperatively.     

Spinal Cord Injury Pain: Mechanisms and Management

Patients with spinal cord injury (SCI) may experience several types of chronic pain, including peripheral and central neuropathic pain, pain secondary to overuse, painful muscle spasms, and visceral pain. An accurate classification of the patient's pain is important for choosing the optimal treatment strategy. In particular, neuropathic pain appears to be persistent despite various treatment attempts. In recent years, we have gained increasing knowledge of SCI pain mechanisms from experimental models and clinical studies. Nevertheless, treatment remains difficult and inadequate. In line with the recommendations for peripheral neuropathic pain, evidence from randomized controlled treatment trials suggests that tricyclic antidepressants and pregabalin are first-line treatments. This review highlights the diagnosis and classification of SCI pain and recent improvements in the understanding of underlying mechanisms, and provides an update on treatment of SCI pain.     

Warfarin-related epidural hematoma: a case report

Spinal epidural hematomas are rare, with trauma being the most common cause. Spinal epidural hematomas caused by coagulation dysfunction are even rarer; however, long-term warfarin therapy increases the risk. The clinical manifestations of spinal epidural hematoma are neurological deficits below the corresponding spinal cord segment level. Magnetic resonance imaging (MRI) is the preferred method for diagnosis, and the main treatment for epidural hematoma with typical symptoms is urgent decompression of the lumbar spine. We describe an almost 80-year-old female patient who received long-term oral warfarin therapy for atrial fibrillation. She developed sudden onset waist pain, and 2 days later, she developed pain and weakness in both lower limbs. Computed tomography (CT) of the thoracolumbar spine showed no obvious hematoma. Eight days after admission, contrast-enhanced CT of the thoracolumbar spine showed intraspinal hematomas at T5–T8 and T12–L2 levels. We performed T3–T7 laminectomy, T5–T8 hematoma removal, and spinal dural repair. The clinical symptoms did not improve significantly, postoperatively. The low incidence of spinal epidural hematoma after anticoagulation treatment means this condition is not recognized timely, and it is misdiagnosed easily. Clinicians should consider this condition when patients treated with anticoagulants have neurological deficits below a spinal segmental plane.     

Longstanding neuropathic pain after spinal cord injury is refractory to transcranial direct current stimulation: A randomized controlled trial

Neuropathic pain remains one of the most difficult consequences of spinal cord injury (SCI) to manage. It is a major cause of suffering and adds to the physical, emotional, and societal impact of the injury. Despite the use of the best available treatments, two thirds of people experiencing neuropathic pain after SCI do not achieve satisfactory pain relief. This study was undertaken in response to a recent clinical trial reporting short-term, clinically significant reductions in neuropathic SCI pain with primary motor cortex transcranial direct current stimulation (tDCS). In this investigation, we aimed to build on this previous clinical trial by extending the assessment period to determine the short-, medium-, and long-term efficacy of tDCS for the treatment of neuropathic pain after SCI. We found that, contrary to previous reports, after 5 tDCS treatment periods, mean pain intensity and unpleasantness rating were not significantly different from initial assessment. That is, in this trial tDCS did not provide any pain relief in subjects with neuropathic SCI pain (n = 10). A similar lack of effect was also seen after sham treatment. Because the injury duration in this study was significantly greater than that of previous investigations, it is possible that tDCS is an effective analgesic only in individuals with relatively recent injuries and pain. Future investigations comparing a range of injury durations are required if we are to determine whether this is indeed the case.     

不同磁共振成像序列在颈髓损伤中的应用比较

目的 比较常规MRI序列、梯度回波T2*加权成像(T2*WI)及磁敏感加权成像(susceptibility weighted imaging,SWI)在急性颈髓损伤(SCI)中的应用价值.方法 对16例有急性颈椎外伤病史的患者,均采用3T MRI (TrioTim,Siemens Medical Solution)行...     

Combined approaches for the relief of spinal cord injury-induced neuropathic pain

The adequate treatment of spinal cord injury (SCI)-induced neuropathic pain still remains an unresolved problem. The current medications predominantly used in the SCI-induced neuropathic pain therapy are morphine, anticonvulsants, antidepressants, and antiepileptics, which suggests that psychiatric aspects might be important factors in the treatment of neuropathic pain.It is well documented that the modulation of the sensory events is not a unique way for achieving pain relief. In addition, pain patients still express dissatisfaction and complain of unwanted effects of the medications, suggesting that alternative approaches for the treatment of neuropathic pain are essential. In psychiatry, pain relief represents relaxation and a feeling of comfort and satisfaction, which suggests that cognitive and emotional motivations are important factors in the treatment of neuropathic pain. The comorbidity of chronic pain and psychiatric disorders, which is well recognized, suggests that the effective therapeutic relief for neuropathic pain induced by SCI can be achieved in conjunction with the management of the sensory and psychiatric aspects of patient.In this review, we address the feasibility of a combined acupuncture and pharmacotherapy treatment for the relief of neuropathic pain behavior following SCI.     

减重平板训练对脊髓损伤大鼠神经病理性疼痛及脊髓后角谷氨酸脱羧酶-65/67表达的影响

目的 探讨减重平板训练对脊髓损伤大鼠神经病理性疼痛及脊髓后角内谷氨酸脱羧酶-65/67(GAD-65/67)表达的影响.方法 将24只Sprague-Dawley大鼠随机分为假手术组(Sham组)、脊髓损伤-不运动组(SCI-Sed组)和脊髓损伤-运动组(SCI-Ex组),每组8只.采用Allen法制作T10不完全性脊...     

脊髓损伤后神经性疼痛患者大脑结构和功能变化的MRI研究进展

脊髓损伤（SCI）后,除感觉运动功能障碍外,神经性疼痛（NP）也是严重影响患者生活质量的主要因素,其发病机理尚不清楚,目前缺乏有效治疗手段。随着影像学技术的发展,SCI后大脑结构和功能改变对NP影响的逐渐被认识,不仅有利于从宏观上揭示NP的病理机制,且为治疗提供了新的思路。本文对SCI后NP患者大脑结构和功能变化及其可能机制进行综述。     

Collagen scaffold combined with human umbilical cord‐derived mesenchymal stem cells promote functional recovery after scar resection in rats with chronic spinal cord injury

Effective therapeutic strategies for treating chronic spinal cord injury (SCI) are currently unavailable. Scar tissue in the lesion area is a main inhibitory factor for axonal regeneration and repair of chronic SCI. In this study, scar tissue was surgically resected from adult rats with 12 week chronic SCI and then collagen scaffold (NeuroRegen Scaffold; NRS) and human umbilical cord‐derived mesenchymal stem cells (hUC‐MSCs) were implanted into the resected cavity to repair chronic SCI. The results demonstrated that the locomotor function of rats was not affected by surgical scar resection, indicating its safety in treating chronic SCI. Implanting NRS and hUC‐MSCs promoted locomotion in rats and improved cortical motor‐ and somatosensory‐evoked potentials. Furthermore, implanting NRS and hUC‐MSCs promoted neurofilament‐ and β‐tubulin‐III‐positive neural regeneration and remyelination, elicited β‐tubulin‐III‐positive neuron production in the lesion area and blocked astrocyte growth outside the lesion area. In conclusion, implanting NRS in combination with hUC‐MSCs provided a beneficial microenvironment for neural regeneration, showing significant therapeutic effects for chronic SCI.