TY - JOUR AU - Chen, Lunhao AU - Hu, Yaling AU - Wang, Siyuan AU - Cao, Kelei AU - Mai, Weihao AU - Sha, Weilin AU - Ma, Huan AU - Zeng, Ling-Hui AU - Xu, Zhen-Zhong AU - Gao, Yong-Jing AU - Duan, Shumin AU - Wang, Yue AU - Gao, Zhihua T1 - mTOR–neuropeptide Y signaling sensitizes nociceptors to drive neuropathic pain PY - 2022/11/22/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.159247 VL - 7 IS - 22 UR - https://doi.org/10.1172/jci.insight.159247 PB - The American Society for Clinical Investigation ER -