The Opioid Receptor Influences Circadian Rhythms in Human Keratinocytes Through the β-Arrestin Pathway

This study investigates the role of the delta opioid receptor (DOPr) in regulating circadian rhythms in human keratinocytes through the β-arrestin pathway. Activation of DOPr with Met-enkephalin caused a 5.6-hour phase shift in the expression of the PER2 gene and altered the expression of clock-controlled genes DBP and Tef. Mechanistically, DOPr and β-arrestin-1 co-localized in the nucleus, enhancing β-arrestin-1 binding to the PER2 promoter and histone H4 acetylation. DOPr knockdown disrupted PER2 rhythmicity, indicating DOPr's essential role in maintaining circadian rhythms. These findings suggest that DOPr influences circadian regulation and could be a potential target for treating circadian rhythm disorders, skin cancer, and impaired wound healing.