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Many epigenetic regulators are involved in pain-associated spinal plasticity. Coactivator-associated arginine methyltransferase 1 (CARM1), an epigenetic regulator of histone arginine methylation, is a highly interesting target in neuroplasticity. However, its potential contribution to spinal plasticity-associated neuropathic pain development remains poorly explored. Here, we report that nerve injury decreased the expression of spinal CARM1 and induced allodynia. Moreover, decreasing spinal CARM1 expression by Fbxo3-mediated CARM1 ubiquitination promoted H3R17me2 decrement at the K+ channel promoter, thereby causing K+ channel epigenetic silencing and the development of neuropathic pain. Remarkably, in naïve rats, decreasing spinal CARM1 using CARM1 siRNA or a CARM1 inhibitor resulted in similar epigenetic signaling and allodynia. Furthermore, intrathecal administration of BC-1215 (a novel Fbxo3 inhibitor) prevented CARM1 ubiquitination to block K+ channel gene silencing and ameliorate allodynia after nerve injury. Collectively, the results reveal that this newly identified spinal Fbxo3-CARM1-K+ channel gene functional axis promotes neuropathic pain. These findings provide essential insights that will aid in the development of more efficient and specific therapies against neuropathic pain. © 2021. The American Society for Experimental NeuroTherapeutics, Inc.

Citation

Ming-Chun Hsieh, Yu-Cheng Ho, Cheng-Yuan Lai, Hsueh-Hsiao Wang, Po-Sheng Yang, Jen-Kun Cheng, Gin-Den Chen, Soo-Cheen Ng, An-Sheng Lee, Kuang-Wen Tseng, Tzer-Bin Lin, Hsien-Yu Peng. Blocking the Spinal Fbxo3/CARM1/K+ Channel Epigenetic Silencing Pathway as a Strategy for Neuropathic Pain Relief. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2021 Apr;18(2):1295-1315

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PMID: 33415686

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