Histone methylation-mediated microRNA-32-5p down-regulation in sensory neurons regulates pain behaviors via targeting Cav3.2 channels

microRNA (miRNA)–mediated gene regulation has been studied as a therapeutic approach, but its functional regulatory mechanism in neuropathic pain is not well understood. Here, we identify that miRNA-32-5p (miR-32-5p) is a functional RNA in regulating trigeminal-mediated neuropathic pain. High-throug...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 119; no. 14; p. e2117209119
Main Authors Qi, Renfei, Cao, Junping, Sun, Yufang, Li, Yanping, Huang, Zitong, Jiang, Dongsheng, Jiang, Xing-Hong, Snutch, Terrance P, Zhang, Yuan, Tao, Jin
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 05.04.2022
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Summary:microRNA (miRNA)–mediated gene regulation has been studied as a therapeutic approach, but its functional regulatory mechanism in neuropathic pain is not well understood. Here, we identify that miRNA-32-5p (miR-32-5p) is a functional RNA in regulating trigeminal-mediated neuropathic pain. High-throughput sequencing and qPCR analysis showed that miR-32-5p was the most down-regulated miRNA in the injured trigeminal ganglion (TG) of rats. Intra-TG injection of miR-32-5p agomir or overexpression of miR-32-5p by lentiviral delivery in neurons of the injured TG attenuated established trigeminal neuropathic pain. miR-32-5p overexpression did not affect acute physiological pain, while miR-32-5p down-regulation in intact rats was sufficient to cause pain-related behaviors. Nerve injury increased the methylated histone occupancy of binding sites for the transcription factor glucocorticoid receptor in the miR-32-5p promoter region. Inhibition of the enzymes that catalyze H3K9me2 and H3K27me3 restored the expression of miR-32-5p and markedly attenuated pain behaviors. Further, miR-32-5p–targeted Cav3.2 T-type Ca2+ channels and decreased miR-32-5p associated with neuropathic pain caused an increase in Cav3.2 protein expression and T-type channel currents. Conversely, miR-32-5p overexpression in injured TG suppressed the increased expression of Cav3.2 and reversed mechanical allodynia. Together, we conclude that histone methylation-mediated miR-32-5p down-regulation in TG neurons regulates trigeminal neuropathic pain by targeting Cav3.2 channels.
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Edited by Hee-Sup Shin, Institute for Basic Science, Daejeon, South Korea; received September 23, 2021; accepted January 13, 2022
1R.Q., J.C., and Y.S. contributed equally to this work.
Author contributions: J.T. designed research; R.Q., J.C., Y.S., Y.L., Z.H., and Y.Z. performed research; R.Q., J.C., Y.S., Y.L., Z.H., X.-H.J., Y.Z., and J.T. analyzed data; and J.C., D.J., T.P.S., and J.T. wrote the paper.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2117209119