Abstract Opioid medications have been widely prescribed in efforts to control medical and surgical pain, but opioid use disorder (OUD) has become a serious, prevalent, and costly public health problem. Identifying risk factors for the development of OUD after prescribed opioid use could help reduce serious injury and mortality-related outcomes, like overdose. Hippocampal (Hpc)-circuit based context processing is an important neuro-cognitive process associated with OUD. Evidence for context processing deficits is seen in psychiatric, substance use, and chronic pain populations. One major predictor of adult OUD that is also linked to context processing is adverse childhood experiences (ACEs). ACEs predict high OUD rates and are associated with complex co- morbidity (e.g., chronic pain, psychiatric conditions, other substance use disorders) that complicates treatment for OUD. ACEs also compromise Hpc function through detrimental effects of stress hormones on Hpc neurons. Thus, ACEs may lead to Hpc circuitry dysfunction and context processing deficits, providing a shared pathway to chronic pain, prescribed opioid use, and OUD development. This Katz R01 will utilize the PI’s expertise in neurocognitive mechanisms of trauma to provide the first direct examination of a mechanistic pathway of risk for OUD that involves links between ACEs and context processing deficits. We will examine 75 adults with OUD taking the prescription opioid agonist buprenorphine (BUP) and compare them to two control groups: 75 adults without OUD taking BUP and 75 adults without OUD and not taking BUP, in a cross-sectional study. We will use a well-validated context processing paradigm to interrogate Hpc structure and function and behavioral performance. Validated self-report and objective measures of opioid misuse, OUD, and ACEs will be used to examine links between ACEs, context processing, and OUD. Our specific aims include: 1) identifying Hpc- circuit based context processing deficits in OUD, independent of opioid agonist effects; 2) establishing links between ACEs, context processing, and OUD severity; and 3) exploring how common symptom domains are associated with ACEs, context processing, and OUD. The findings from this project will lead to longitudinal work with the potential to trace a mechanistic pathway that helps explain co-morbidities between chronic pain, stress-related disorders, and OUD development after prescribed opioid use. This may ultimately open new doors to discovery of prevention and treatment paradigms that will identify those at risk when opioids are prescribed (high ACEs, poor context processing), and ultimately shape neuroscience-informed ways to remediate functional deficits even after they have developed.