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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 4

Ablation of Mtor in microglia reduces microgliosis but does not affect neuropathic pain in male or female mice.

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Ablation of Mtor in microglia reduces microgliosis but does not affect n...
(A) Experimental schedule showing the selected Mtor deletion in microglia and pain tests. (B) Representative images showing immunofluorescence labeling of Iba1 and p-S6 in ipsilateral SDH at day 7 after SNI in Cx3cr1CreER/+:Mtorfl/fl or control mice (Cx3cr1CreER/+ mice with TAM and Cx3cr1CreER/+:Mtorfl/fl mice with Veh). Arrows indicating Iba1+ p-S6+ microglia. Scale bar: 20 μm. (C) Representative images of bilateral SDH microglia (Iba1+) in Cx3cr1CreER/+:Mtorfl/fl mice with TAM or in control mice at day 7 after SNI. Scale bar: 100 μm. (D) Quantification of microglia in the ipsilateral and contralateral SDH in Cx3cr1CreER/+:Mtorfl/fl and control mice at day 7 after SNI (n = 5–7 per group). (E) Representative images of the ipsilateral SDH showing colocalization of Iba1 and BrdU (arrows) at day 7 after SNI. Boxes show regions of higher magnification in the SDH. Scale bars: 100 and 20 μm for low- and high-magnification images, respectively. (F) Quantitation of mitotic microglia (Iba1+BrdU+) in SDH in Cx3cr1CreER/+:Mtorfl/fl and control mice at day 7 after SNI (n = 5–7 mice per group). (G–I) Measurements of mechanical allodynia (G), heat hyperalgesia (H), and cold allodynia (I) in Cx3cr1CreER/+:Mtorfl/fl and control mice before and after SNI (n = 10–13 mice per group; male and female mice were merged). Data are shown as mean ± SEM. **P < 0.01 and ***P < 0.001, by 1-way AVOVA (F) or 2-way ANOVA followed by Bonferroni’s post hoc tests among groups (D and G–I). TAM, tamoxifen; Veh, vehicle; Cont, contralateral; Ipsi, ipsilateral; PWT, paw withdraw threshold; PWL, paw withdraw latency; D, day.

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