POMC mediates orofacial hyperalgesia under hypoestrogenic conditions

Estrogen modulates sensory neuron excitability via metabolic pathways, regulating women's pain perception. pro-opiomelanocortin (POMC), an endogenous polypeptide precursor, regulates pain response and is highly expressed in the trigeminal ganglion (TG). In this study, we used ovariectomized female rats to study how trigeminal ganglion POMC links to orofacial allodynia in hypoestrogenic state, and verified at both the gene and protein levels that the expression of POMC in the trigeminal ganglion decreased under the hypoestrogenic state. Subsequently, overexpressing the POMC gene in the TG reversed the pain hyperalgesia in ovariectomized rats. To further explore the regulatory mechanism of estrogen on POMC, we injected a selective estrogen receptor agonist at the trigeminal ganglion. Estradiol (E2) in the TG regulates the expression of POMC through estrogen receptor α (ERα). Subsequently, the Chromatin Cleavage and Tagging technology (CUT&Tag) and the dual-luciferase assay revealed that estrogen receptor α in the trigeminal ganglion has a positive regulatory effect on the promoter of POMC. In conclusion, this study has found that in the trigeminal ganglion, estrogen receptor α may reduce the expression of the POMC gene by inhibiting the activity of the POMC promoter. Meanwhile, this study has also found that in the TG, ERα may further regulate the biological activity of the POMC protein by binding to it. This dual regulation at both the transcriptional level and the protein level collectively mediates a decrease in the orofacial mechanical pain threshold and triggers an orofacial allodynia response.