UCLA

Opioid Use Disorder (OUD) is highly comorbid with post-traumatic stress disorder (PTSD) and chronic pain, resulting in exacerbated symptoms and poorer treatment outcomes. Studying each of these disorders in isolation fails to capture the complexity of the interrelationships between OUD and PTSD/chronic pain. OUD, PTSD and chronic pain share common symptomology, risk factors, and impacted neurocircuitry, suggesting that these disorders share common mechanistic pathways that cross-sensitize and influence each other. For instance, OUD, PTSD and chronic pain are all marked by altered learning mechanisms that impact the pathophysiology of these disorders. Additionally, alterations in the dynorphin/kappa opioid receptor (KOR) system caused by stress and chronic pain are an emerging target for OUD comorbidities, due to involvement of this system in negative affect and stress-induced relapse of drug seeking. The goal of this presented dissertation is to shed light on the stress- and pain-induced neuroadaptations that may promote vulnerability for enhanced opioid learning and reward. In Chapter 2, a rodent model of PTSD was utilized to test the impact of unpredictable stress on opioid-induced locomotion and opioid-context learning. We found that while unpredictable stress had no impact on subsequent morphine reward learning, it sensitized the locomotor response to low dose morphine. Interestingly, unpredictable stress also induced preference to contexts previously paired with low dose naltrexone, an opioid receptor antagonist that is typically considered aversive. In Chapter 3, a chronic neuropathic pain model was utilized to test the impact of neuropathic pain on KOR agonist-induced reinstatement of oxycodone place preference. Here, we found that KOR agonism-induced reinstatement in neuropathic pain females, but not neuropathic pain males, supporting previous findings that chronic pain-induced changes in the dynorphin/KOR system are sexually dimorphic. We additionally found a relationship between the magnitude of the reinstatement and mechanical withdrawal thresholds in neuropathic pain females. Specifically, females with greater mechanical allodynia had greater subsequent reinstatement of oxycodone place preference. Overall, this work underscores the need for integrated approaches to address the intricate interplay between OUD, PTSD, and chronic pain comorbidities.