Investigation of the mechanisms and curatives for chronic pain based on the remote activation of supraspinal glial cells.

神经损伤引起的神经性疼痛是一种难以用镇痛药治疗的慢性疼痛。本研究旨在利用部分坐骨神经结扎小鼠模型揭示神经性疼痛的棘上机制。预先给予l型钙通道α2δ亚基阻滞剂加巴喷丁可逆转神经结扎小鼠的机械性痛觉过敏，但损伤后无逆转作用。提示中央给药加巴喷丁可减轻神经性疼痛的发展，但不能维持神经性疼痛。接下来，我们检查了几个大脑区域中神经元细胞的表达。我们观察到小胶质细胞标志物Iba-1和星形胶质细胞标志物GFAP在前扣带皮层（ACC）的表达增加。小胶质细胞抑制剂米诺环素在ACC内治疗减轻了神经结扎小鼠的痛觉过敏，提示ACC内小胶质细胞的激活参与了神经性疼痛痛觉过敏的表达。此外，抑制ACC小胶质细胞也会减弱星形胶质细胞的激活。此外，神经结扎过程中AMPA受体亚基GluA1在ser831位点磷酸化的增加，被二甲胺四环素在acc内治疗所减弱。因此，神经结扎过程中ACC小胶质细胞的激活可能参与了神经性疼痛的发生，并通过增强的谷氨酸能功能介导。

Neuropathic pain that results from the nerve injury is the chronic pain that is hard to treat with analgesics. The present study was designed to reveal the supraspinal mechanisms of neuropathic pain using partial sciatic nerve-ligated mouse model. The mechanical hyperalgesia in nerve-ligated mice were reversed by the preemptive, but not postinjury, administration of L-type calcium channel α2δsubunit blocker gabapentin. It is suggested that centrally administered gabapentin attenuates the development, but not maintenance of neuropathic pain. In the next, we examined the expression of neuronal cells in several brain regions. We observed that the expressions of Iba-1 that is a marker of microglia and GFAP that is a marker of astrocyte were increased in the anterior cingulate cortex (ACC). Intra-ACC treatment with microglial inhibitor minocycline attenuated the hyperalgesia in nerve-ligated mice, suggesting that the activation of microglia in the ACC is involved in the expression of hyperalgesia in neuropathic pain. Moreover, inhibition of the ACC microglia also attenuate the activation of astrocytes. Furthermore, the increased phosphorylation of AMPA receptor subunit GluA1 at ser831 in nerve-ligation is attenuated by the intra-ACC treatment with minocycline. Therefore, it is possible that the ACC microglial activation in nerve-ligation is involved in the neuropathic pain, which is mediated by the enhanced glutamatergic function.