Mei Xiao-Peng, Zhou Yang, Wang Wei, Tang Jun, Wang Wen, Zhang Hui, Xu Li-Xian, Li Yun-Qing
Department of Anesthesiology, School of Stomatology, Fourth Military Medical University, Xi'an, PR China.
Neurosignals. 2011;19(1):44-53. doi: 10.1159/000324293. Epub 2011 Mar 9.
Reports suggest that microglia play a key role in spinal nerve ligation (SNL)-induced neuropathic pain, and toll-like receptor 3 (TLR3) has a substantial role in the activation of spinal microglia and the development of tactile allodynia after nerve injury. In addition, ketamine application could suppress microglial activation in vitro, and ketamine could inhibit proinflammatory gene expression possibly by suppressing TLR-mediated signal transduction. Therefore, the present study was designed to disclose whether intrathecal ketamine could suppress SNL-induced spinal microglial activation and exert some antiallodynic effects on neuropathic pain by suppressing TLR3 activation. Behavioral results showed that intrathecal ketamine attenuated SNL-induced mechanical allodynia, as well as spinal microglial activation, in a dose-dependent manner. Furthermore, Western blot analysis displayed that ketamine application downregulated SNL-induced phosphorylated-p38 (p-p38) expression, which was specifically expressed in spinal microglia but not in astrocytes or neurons. Besides, ketamine could reverse TLR3 agonist (polyinosine-polycytidylic acid)-induced mechanical allodynia and spinal microglia activation. It was concluded that intrathecal ketamine depresses TLR3-induced spinal microglial p-p38 mitogen-activated protein kinase pathway activation after SNL, probably contributing to the antiallodynic effect of ketamine on SNL-induced neuropathic pain.
报告表明，小胶质细胞在脊髓神经结扎（SNL）诱导的神经性疼痛中起关键作用，而Toll样受体3（TLR3）在神经损伤后脊髓小胶质细胞的激活以及触觉异常性疼痛的发展中起重要作用。此外，氯胺酮在体外可抑制小胶质细胞的激活，并且氯胺酮可能通过抑制TLR介导的信号转导来抑制促炎基因的表达。因此，本研究旨在揭示鞘内注射氯胺酮是否能抑制SNL诱导的脊髓小胶质细胞激活，并通过抑制TLR3激活对神经性疼痛发挥某种抗痛觉过敏作用。行为学结果表明，鞘内注射氯胺酮以剂量依赖性方式减轻了SNL诱导的机械性异常性疼痛以及脊髓小胶质细胞的激活。此外，蛋白质印迹分析显示，应用氯胺酮可下调SNL诱导的磷酸化p38（p-p38）表达，p-p38在脊髓小胶质细胞中特异性表达，而在星形胶质细胞或神经元中不表达。此外，氯胺酮可逆转TLR3激动剂（聚肌苷酸-聚胞苷酸）诱导的机械性异常性疼痛和脊髓小胶质细胞激活。得出的结论是，鞘内注射氯胺酮可抑制SNL后TLR3诱导的脊髓小胶质细胞p-p38丝裂原活化蛋白激酶途径的激活，这可能是氯胺酮对SNL诱导的神经性疼痛产生抗痛觉过敏作用的原因。
