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

Beta-endorphinergic neurons in the hypothalamic arcuate nucleus (ARC) synthesize beta-endorphin (ß-EP) to alleviate nociceptive behaviors, although the underlying regulatory mechanisms remain unknown. Here, we elucidated a novel epigenetic pathway driven by microRNA regulation of beta-endorphin 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, histone deacetylase 9 downregulation increased acetylation of histone H3 lysine-18, facilitating the binding of NR4A2 transcription factor to the miR-203a-3p gene promoter increasing miR-203a-3p expression following nerve injury. 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 ß-EP. Our findings highlight an epigenetic regulatory pathway for ß-EP synthesis that contributes to neuropathic pain development and maintenance mechanisms providing for new therapeutic targets for neuropathic pain treatment. Overall design: Hypothalamic arcuate nucleus miRNA profiles in rat ARC tissue on day 14 after CCI-ION (n=3) or sham operation (n=3)