@article{10.1172/jci.insight.159247, author = {Lunhao Chen AND Yaling Hu AND Siyuan Wang AND Kelei Cao AND Weihao Mai AND Weilin Sha AND Huan Ma AND Ling-Hui Zeng AND Zhen-Zhong Xu AND Yong-Jing Gao AND Shumin Duan AND Yue Wang AND Zhihua Gao}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {mTOR–neuropeptide Y signaling sensitizes nociceptors to drive neuropathic pain}, year = {2022}, month = {11}, volume = {7}, url = {https://insight.jci.org/articles/view/159247}, abstract = {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.}, number = {22}, doi = {10.1172/jci.insight.159247}, url = {https://doi.org/10.1172/jci.insight.159247}, }