The small GTPase Ras homolog enriched in the brain (Rheb) can activate mammalian target of rapamycin (mTOR) and regulate the growth and cell cycle progression. We investigated the role of Rheb-mediated mTORC1 signaling in neuropathic pain. A chronic constriction injury (CCI) model was dopted. CCI induced obvious spinal Rheb expression and phosphorylation of mTOR, S6, and 4-E-BP1. Blocking mTORC1 signal with rapamycin alleviated the neuropathic pain and restored morphine efficacy in CCI model. Immunofluoresence showed a neuronal co-localization of CCI-induced Rheb and pS6. Rheb knockin mouse showed a similar behavioral phenotype as CCI. In spinal slice recording, CCI increased the firing frequency of neurons expressing HCN channels; inhibition of mTORC1 with rapamycin could reverse the increased spinal neuronal activity in neuropathic pain. Spinal Rheb is induced in neuropathic pain, which in turn active the mTORC1 signaling in CCI. Spinal Rheb-mTOR signal plays an important role in regulation of spinal sensitization in neuropathic pain, and targeting mTOR may give a new strategy for pain management.

大脑中富集的小 GTPase Ras 同源物 (Rheb) 可以激活哺乳动物雷帕霉素靶标 (mTOR) 并调节生长和细胞周期进程。我们研究了 Rheb 介导的 mTORC1 信号在神经性疼痛中的作用。采用慢性缩窄性损伤（CCI）模型。CCI 诱导明显的脊髓 Rheb 表达和 mTOR、S6 和 4-E-BP1 的磷酸化。用雷帕霉素阻断 mTORC1 信号可减轻 CCI 模型中的神经性疼痛并恢复吗啡的功效。免疫荧光显示 CCI 诱导的 Rheb 和 pS6 的神经元共定位。Rheb 敲入小鼠表现出与 CCI 相似的行为表型。在脊髓切片记录中，CCI 增加了表达 HCN 通道的神经元的放电频率；用雷帕霉素抑制 mTORC1 可以逆转神经性疼痛中脊髓神经元活动的增加。脊髓 Rheb 在神经性疼痛中被诱导，进而激活 CCI 中的 mTORC1 信号传导。脊髓 Rheb-mTOR 信号在调节神经性疼痛中的脊髓致敏中起重要作用，靶向 mTOR 可能为疼痛管理提供新的策略。