Epigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model

Yu Tao, Yuan Zhang, Xiaohong Jin, Nan Hua, Hong Liu, Renfei Qi, Zitong Huang, Yufang Sun, Dongsheng Jiang, Terrance P. Snutch, Xinghong Jiang and Jin Tao ()
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Yu Tao: Suzhou Medical College of Soochow University
Yuan Zhang: The Second Affiliated Hospital of Soochow University
Xiaohong Jin: The First Affiliated Hospital of Soochow University
Nan Hua: Suzhou Medical College of Soochow University
Hong Liu: The First Affiliated Hospital of Soochow University
Renfei Qi: Suzhou Medical College of Soochow University
Zitong Huang: Suzhou Medical College of Soochow University
Yufang Sun: Suzhou Medical College of Soochow University
Dongsheng Jiang: Helmholtz Zentrum München
Terrance P. Snutch: University of British Columbia
Xinghong Jiang: Suzhou Medical College of Soochow University
Jin Tao: Suzhou Medical College of Soochow University

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: Abstract Although beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (β-EP) to alleviate nociceptive behaviors, the underlying regulatory mechanisms remain unknown. Here, we elucidated an epigenetic pathway driven by microRNA regulation of β-EP synthesis in ARC neurons to control neuropathic pain. In pain-injured rats miR-203a-3p was the most highly upregulated miRNA in the ARC. A similar increase was identified in the cerebrospinal fluid of trigeminal neuralgia patients. Mechanistically, we found histone deacetylase 9 was downregulated following nerve injury, which decreased deacetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter, thereby upregulating miR-203a-3p expression. Further, increased miR-203a-3p was found to maintain neuropathic pain by targeting proprotein convertase 1, an endopeptidase necessary for the cleavage of proopiomelanocortin, the precursor of β-EP. The identified mechanism may provide an avenue for the development of new therapeutic targets for neuropathic pain treatment.

Date: 2023
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DOI: 10.1038/s41467-023-43022-7

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