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病理性疼痛是一种难以用镇痛剂治疗的慢性疼痛。本研究旨在通过部分坐骨神经结扎的小鼠模型来揭示神经病理性疼痛的脊髓上机制。预先给予L类钙通道α2δ亚单位阻断剂加巴喷丁，可逆转神经结扎小鼠的机械性痛敏反应，但不能逆转损伤后的痛敏反应。研究表明，中央给药加巴喷丁可以延缓神经病理性疼痛的发展，但不能维持神经病理性疼痛。在接下来的研究中，我们研究了几个脑区神经细胞的表达。我们观察到小胶质细胞的标记物Iba-1和星形胶质细胞的标记物GFAP在前扣带回皮质(ACC)的表达增加。注射小胶质细胞抑制剂米诺环素可减轻神经结扎小鼠的痛敏反应，提示小胶质细胞的激活参与了神经病理性疼痛中痛觉过敏的表达。此外，抑制ACC小胶质细胞也可减弱星形胶质细胞的激活。此外，在神经结扎中AMPA受体亚单位GluA1在Ser831位的磷酸化增加可被米诺环素在ACC内处理减弱。因此，神经结扎时ACC小胶质细胞的激活可能参与了神经病理性疼痛的发生，其机制可能是通过增强谷氨酸能功能来实现的。

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.