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mTOR–neuropeptide Y signaling sensitizes nociceptors to drive neuropathic pain
Lunhao Chen, … , Yue Wang, Zhihua Gao
Lunhao Chen, … , Yue Wang, Zhihua Gao
Published October 4, 2022
Citation Information: JCI Insight. 2022;7(22):e159247. https://doi.org/10.1172/jci.insight.159247.
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Research Article Neuroscience

mTOR–neuropeptide Y signaling sensitizes nociceptors to drive neuropathic pain

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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.

Authors

Lunhao Chen, Yaling Hu, Siyuan Wang, Kelei Cao, Weihao Mai, Weilin Sha, Huan Ma, Ling-Hui Zeng, Zhen-Zhong Xu, Yong-Jing Gao, Shumin Duan, Yue Wang, Zhihua Gao

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Figure 1

Activation of the mTOR in subsets of DRG neurons and SDH microglia after spared nerve injury (SNI).

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Activation of the mTOR in subsets of DRG neurons and SDH microglia after...
(A) A schematic diagram depicting the isolation of DRGs and SDH. (B) Representative blots indicating the upregulated p-S6 levels in the ipsilateral DRG after SNI at indicated time points. (C) Quantification of p-S6/S6 in the ipsilateral DRG at indicated time points after SNI (n = 4–7 mice per time point). (D) Coimmunostaining p-S6 with CGRP, NF160/200, or IB4 in DRGs after SNI (arrows indicating colabeled neurons). Scale bar: 50 μm. (E–G) Quantification of p-S6+ neurons in different subpopulations of DRG neurons: CGRP (E), NF160/200 (F), and IB4 (G) (n = 4 mice). (H) Representative blots of p-S6 and S6 levels in SDH (L4 and L5) at days 3 and day 7 after SNI. (I) Quantification of p-S6/S6 in the ipsilateral and contralateral SDH (n = 5 and 3 for day 3 and day 7 after SNI, respectively). (J) Representative images of p-S6+ microglia (arrows) in the superficial contralateral and ipsilateral SDH (dotted lines) at indicated time points after SNI. Boxes show regions of higher magnification in the SDH. Scale bars: 100 and 20 μm for low- and high-magnification images, respectively. (K) Quantification of p-S6+ microglia in superficial SDH (n = 5–6 mice per time point). Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, 2-tailed paired Student’s t tests. BL, baseline; Ipsi, ipsilateral; Cont, contralateral; DRG: dorsal root ganglion; SDH, spinal dorsal horn.

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