Chronic stress exposure confers risk for chronic post traumatic musculoskeletal pain through DNA methylation changes at the POMC promoter

Chronic posttraumatic musculoskeletal pain (CPMP) is a prevalent and debilitating outcome of traumatic stress exposure (TSE). Chronic stress is a major risk factor for CPMP and prior work suggests it may blunt the acute cortisol response to TSE that impedes recovery. We previously found that hypermethylation in the promoter of POMC, a key regulator of cortisol production, predicts CPMP. Here, we aimed to validate this relationship and examine how chronic stress influences epigenetic regulation of POMC, POMC mRNA expression, and cortisol levels. Pain, stress, and biological data (n=705) were drawn from AURORA, a longitudinal observational study of TSE survivors. DNA methylation, mRNA expression, and cortisol were measured from blood collected within 72 hours of TSE. To evaluate mechanistic pathways, we tested associations between chronic stress (Area Deprivation Index), POMC methylation, POMC mRNA, cortisol, and pain. In parallel, we assessed changes in POMC methylation and expression in an in vitro model of chronic stress (100nM cortisol for 51 days). Consistent with prior findings, higher POMC promoter methylation was associated with more severe CPMP (β=1.165, p=0.008). Increased POMC promoter methylation levels were significantly associated with greater chronic stress (β=11.7, p=0.005), lower POMC expression (β=-2.65, p=0.017), and negatively correlated with peritraumatic cortisol (r=-0.170, p=0.006). Additionally, these patterns were recapitulated in vitro. Individuals who developed CPMP also had higher chronic stress (β=2.49, p=0.013) and lower cortisol (β=-2.05, p=0.042). These findings suggest that chronic stress may impair cortisol production via POMC promoter methylation thereby contributing to CPMP by disrupting cortisol-dependent processes that facilitate pain recovery.