Spine Lab, Department of Orthopedic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Department of Neurobiology and Department of Neurology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
JCI Insight. 2022 Nov 22;7(22):e159247. doi: 10.1172/jci.insight.159247.
Neuropathic pain is a refractory condition that involves de novo protein synthesis in the nociceptive pathway. The mTOR is a master regulator of protein translation; however, mechanisms underlying its role in neuropathic pain remain elusive. Using the spared nerve injury-induced neuropathic pain model, we found that mTOR was preferentially activated in large-diameter dorsal root ganglion (DRG) neurons and spinal microglia. However, selective ablation of mTOR in DRG neurons, rather than microglia, alleviated acute neuropathic pain in mice. We show that injury-induced mTOR activation promoted the transcriptional induction of neuropeptide Y (Npy), likely via signal transducer and activator of transcription 3 phosphorylation. NPY further acted primarily on Y2 receptors (Y2R) to enhance neuronal excitability. Peripheral replenishment of NPY reversed pain alleviation upon mTOR removal, whereas Y2R antagonists prevented pain restoration. Our findings reveal an unexpected link between mTOR and NPY/Y2R in promoting nociceptor sensitization and neuropathic pain.
神经病理性疼痛是一种难治性疾病，涉及伤害感受通路中的新蛋白质合成。mTOR 是蛋白质翻译的主要调节剂；然而，其在神经病理性疼痛中的作用机制仍不清楚。使用 spared nerve injury-induced 神经病理性疼痛模型，我们发现 mTOR 在大直径背根神经节（DRG）神经元和脊髓小胶质细胞中优先激活。然而，选择性地在 DRG 神经元中而不是小胶质细胞中消除 mTOR，可减轻小鼠的急性神经病理性疼痛。我们表明，损伤诱导的 mTOR 激活促进了神经肽 Y（Npy）的转录诱导，可能通过信号转导和转录激活因子 3 的磷酸化。NPY 进一步主要作用于 Y2 受体（Y2R）以增强神经元兴奋性。外周补充 NPY 逆转了 mTOR 去除后的疼痛缓解，而 Y2R 拮抗剂则阻止了疼痛的恢复。我们的研究结果揭示了 mTOR 与 NPY/Y2R 之间在促进伤害感受器敏化和神经病理性疼痛方面的意外联系。
