Lei Yishan, Sun Yuʼe, Lu Cuiʼe, Ma Zhengliang, Gu Xiaoping
From the Department of Anesthesiology, Affiliated Drum Tower Hospital of Medical Department of Nanjing University, Nanjing, China.
Reg Anesth Pain Med. 2016 Nov/Dec;41(6):744-749. doi: 10.1097/AAP.0000000000000441.
Administration of resiniferatoxin (RTX) can mimic the clinical symptoms of postherpetic neuralgia. However, it is unclear whether activated glia contribute to the pathogenesis of RTX-induced neuropathic pain; furthermore, the relationship between p38, N-methyl-D-aspartate receptor type 2B (NR2B) as well as proinflammatory cytokines and activated glia remains unknown.
Intraperitoneal injection of RTX was performed to induce neuropathic pain in rats. Mechanical allodynia and thermal hyperalgesia were assessed by von Frey filaments and a radiant heat stimulus, respectively. Western blot and immunofluorescence labeling examined the expression of NR2B, activated glia markers, p38, and proinflammatory cytokines in the spinal cord. We further investigated the effect of the glial inhibitors, fluorocitrate and minocycline, on nociceptive behaviors and expression of p38, NR2B, and proinflammatory cytokines.
Resiniferatoxin leads to an increase of paw withdrawal latency to a heat stimulus and caused a mechanical allodynia within 2 weeks. The expression of tumor necrosis factor α, IL-1β, p38, and NR2B was up-regulated in RTX-induced neuropathic pain rat model and lasted for at least 49 days. Microglia were activated at the early phase of the disease, whereas activated astrocytes were detected in the sustainment phase. Both minocycline and fluorocitrate attenuated the nociceptive behaviors and expression of related proteins.
Activated glia participate in the pathogenesis of RTX-induced neuropathic pain and are likely to be the source of proinflammatory cytokines. Inhibition of glia contributes to an analgesic effect. These findings provide a novel strategy for the treatment of postherpetic neuralgia.
给予树脂毒素（RTX）可模拟带状疱疹后神经痛的临床症状。然而，尚不清楚活化的神经胶质细胞是否参与RTX诱导的神经性疼痛的发病机制；此外，p38、2B型N-甲基-D-天冬氨酸受体（NR2B）以及促炎细胞因子与活化神经胶质细胞之间的关系仍不清楚。
通过腹腔注射RTX诱导大鼠神经性疼痛。分别用von Frey细丝和热辐射刺激评估机械性异常性疼痛和热痛觉过敏。蛋白质免疫印迹法和免疫荧光标记检测脊髓中NR2B、活化神经胶质细胞标志物、p38和促炎细胞因子的表达。我们进一步研究了神经胶质细胞抑制剂氟代柠檬酸和米诺环素对伤害性反应行为以及p38、NR2B和促炎细胞因子表达的影响。
树脂毒素导致热刺激引起的爪部退缩潜伏期增加，并在2周内引起机械性异常性疼痛。在RTX诱导的神经性疼痛大鼠模型中，肿瘤坏死因子α、白细胞介素-1β、p38和NR2B的表达上调，并持续至少49天。小胶质细胞在疾病早期被激活，而活化的星形胶质细胞在维持期被检测到。米诺环素和氟代柠檬酸均减弱了伤害性反应行为和相关蛋白的表达。
活化的神经胶质细胞参与RTX诱导的神经性疼痛的发病机制，并且可能是促炎细胞因子的来源。抑制神经胶质细胞有助于产生镇痛作用。这些发现为带状疱疹后神经痛的治疗提供了一种新策略。
