Identifying Inflammatory Targets to Prevent Stress-Induced Opioid Seeking in Females

Abstract ID 91660 Poster Board 301 Abstract Text: With over 40 million people exhibiting dependence on opioids, it is undeniable that this epidemic remains highly prevalent. Historically, men have demonstrated a higher rate of opioid use, but women have recently escalated intake of prescription opioids including oxycodone. Further, opioid misuse is associated with stress-related conditions including post-traumatic stress disorder (PTSD). A destructive cycle can occur where reminders of the initial trauma lead to hyperarousal, driving the motivation to seek opioids to alleviate this distress. Importantly, females exhibit higher rates of stress-induced opioid relapse and an increased risk of developing additional mental health conditions and impairments in cardiac health. Thus, investigation into the overlapping mechanisms by which stress and opioids impact the brain and periphary in females will allow us to develop novel sex-specific treatment targets for these conditions. One mechanism involved in the initiation and maintenance of PTSD and substance use disorder is inflammation. Our lab has established that blocking the neuroimmune impact of social stress in females prevents the behavioral and cardiovascular impact of stress. These experiments were designed to further investigate the inflammatory mechanisms by which comorbid oxycodone and stress impact the brain and cardiovascular systems in females to begin to elucidate the underlying etiology of this comorbidity in women. Adult Sprague Dawley female rats were implanted with cardio-telemetric devices to measure heart rate, blood pressure, and heart rate variability (sympathetic/vagal balance) at rest and during oxycodone and stress exposure. Rats were given oxycodone in their drinking water on an intermittent schedule for three weeks to establish stable intake of <30 mg/kg per night (<30 mL intake of 0.3 mg/mL oxycodone) prior to a single acute psychosocial stress exposure using the witness stress (WS) model. In this paradigm, rats are spared the physical aspects of social defeat while experiencing the sensory and psychological components. This model has been identified by our lab and others as a potent stressor, especially in females, that imparts many of its deleterious effects through inflammatory mechanisms. Immediately following WS or control, female rats were given access to oxycodone drinking bottles for a single dark cycle. Brain and heart tissue were then collected to determine the impact of oxycodone on inflammatory markers in discrete brain regions and in cardiac tissue. These experiments determined that three weeks of voluntary oral oxycodone exposure impacted resting heart rate with a correlation between the amount of drug consumed and the reduction in resting heart rate. Additionally, a single acute WS increased the amount of oxycodone consumed during the following dark cycle. These ongoing studies will allow us to identify if the WS-evoked increases in oxycodone drinking exacerbates the inflammatory, behavioral, and cardiovascular consequences of psychosocial stress, fueling the bidirectional comorbidity between opioid abuse and stress-related comorbidities. Future experiments utilizing anti-inflammatory compounds will attempt to alleviate these effects in a translational manner to begin addressing the widespread impact of trauma and opioid abuse in women.