UNDERSTANDING THE LINK BETWEEN TRAUMATIC STRESS AND CHRONIC PAIN: RISK, MECHANISM, AND INTERVENTION

Traumatic stress exposure (TSE) is a leading precipitant of chronic pain and posttraumatic stress disorder (PTSD), yet the biological mechanisms that determine who recovers versus who develops chronic symptoms remain poorly understood. This dissertation integrates human, animal, and molecular data to identify developmental, genomic, and hormonal factors that shape post-trauma outcomes and to test a biologically informed preventative intervention.Chapter 2 establishes early life adversity (ELA) as a major vulnerability factor for chronic posttraumatic musculoskeletal pain (CPMP) in humans. Using data from the AURORA cohort, we found that individuals reporting higher levels of childhood physical abuse, emotional abuse, and bullying were significantly more likely to follow adverse pain trajectories after traumatic stress exposure as adults. These associations remained robust after adjusting for demographic and clinical confounders. Collectively, these findings suggest that early adverse experiences affect stress- and immune-related systems, embedding a latent vulnerability that increases susceptibility to chronic pain and other adverse posttraumatic outcomes in adulthood.Chapter 3 examines acute molecular responses to TSE across eight rat tissues at 2-, 24-, and 72-hours post-stress. Integrative analysis of microRNA (miRNA) and messenger RNA (mRNA) expression revealed coordinated regulation of glucocorticoid signaling, immune activation, and estrogen receptor pathways. These results define a post-trauma plasticity window in which biological processes are highly dynamic and potentially modifiable, highlighting candidate mechanisms linking developmental programming to adult stress outcomes.Chapter 4 translates these insights to a clinical setting through the Post-traumatic Estradiol Administration and Care Evaluation (PEACE) trial, a randomized, placebo-controlled pilot study testing the feasibility of acute estradiol (E2) administration following sexual assault. This chapter is a study protocol which describes how E2, identified as a mechanistically plausible intervention, will be assessed for tolerability and operational feasibility in the emergency care environment.Together, these studies outline a continuum from developmental vulnerability to molecular mechanism to clinical application, providing a framework for biologically targeted prevention of chronic pain and other adverse posttraumatic outcomes.