2. Academic Validation
  3. Epigenetic regulation of beta-endorphin synthesis in hypothalamic arcuate nucleus neurons modulates neuropathic pain in a rodent pain model

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

  • Nat Commun. 2023 Nov 9;14(1):7234. doi: 10.1038/s41467-023-43022-7.
Yu Tao # 1,  Yuan Zhang # 2 3,  Xiaohong Jin # 4,  Nan Hua 1,  Hong Liu 4,  Renfei Qi 1,  Zitong Huang 1,  Yufang Sun 1 3,  Dongsheng Jiang 5,  Terrance P Snutch 6,  Xinghong Jiang 1 3,  Jin Tao 7 8
Affiliations

Affiliations

  • 1 Department of Physiology and Neurobiology & Centre for Ion Channelopathy, Suzhou Medical College of Soochow University, Suzhou, 215123, PR China.
  • 2 Department of Geriatrics & Clinical Research Center of Neurological Disease, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, PR China.
  • 3 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, PR China.
  • 4 Department of Pain Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, PR China.
  • 5 Institute of Regenerative Biology and Medicine, Helmholtz Zentrum München, Munich, 81377, Germany.
  • 6 Michael Smith Laboratories and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
  • 7 Department of Physiology and Neurobiology & Centre for Ion Channelopathy, Suzhou Medical College of Soochow University, Suzhou, 215123, PR China. taoj@suda.edu.cn.
  • 8 Jiangsu Key Laboratory of Neuropsychiatric Diseases, Soochow University, Suzhou, 215123, PR China. taoj@suda.edu.cn.
  • # Contributed equally.
PMID: 37945654 DOI: 10.1038/s41467-023-43022-7
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.

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