Targeting the Renin System for the Treatment of Pain and Opioid Use Disorder

Project Summary ______ Chronic pain is a pervasive condition that impacts an estimated 20% of the population with close to 8% of individuals experiencing high-impact pain that severely restricts daily activities. Opioid analgesics are the most powerful and effective medications for reducing acute pain and are a frontline resource for analgesia in chronic pain patients. However, repeated use of opioids is associated with analgesic tolerance, greater sensitivity to nociceptive and non-nociceptive stimuli (i.e., opioid-induced hyperalgesia/allodynia), and a risk of developing opioid use disorder (OUD). OUD is characterized by an escalation of opioid use over time and a parallel development of intense negative emotional states. Central to this conceptualization is the continued use of opioids to self-medicate both somatic and emotional pain in individuals suffering from OUD. These factors have contributed to the current prescription opioid epidemic, which is a national health crisis hallmarked by skyrocketing reports of opioid misuse and overdose deaths. The elucidation of novel pathophysiological mechanisms driving the escalation of opioid use and opioid-associated pain are desperately needed, spurring the NIH Helping to End Addiction Long-Term (HEAL) initiative to support the early-stage discovery of new pain and OUD targets. For this proposal, we have identified renin inhibition as a highly promising strategy in accord with this initiative, particularly since the FDA-approved renin inhibitor, aliskiren, is clinically available for treating hypertension and well tolerated in most individuals. More recent studies have described a beneficial role for aliskiren to reduce hyperalgesia symptoms in a diabetic neuropathy pain model, although its effects on opioid- related pain are unknown. In preclinical animal models of OUD, we have shown that escalated and extended access to fentanyl produces a profound mechanical allodynia and increased pain avoidance-like behavior in rodents. Our more recent work has shown that extended access (long access, LgA) to self-administered fentanyl produces escalated fentanyl intake and increased motivation for fentanyl in male and female rats compared animals given limited access (short access, ShA) to fentanyl. With this comprehensive model, we are prepared to directly test our overall hypothesis that renin inhibition will reduce the escalation of fentanyl self-administration and significantly alleviate hyperalgesia/allodynia and pain avoidance-like behaviors in fentanyl self-administering animals. This proposal examines an FDA-approved therapeutic strategy (direct renin inhibition) to target an understudied molecule (renin receptor) as a novel therapeutic avenue for the treatment of OUD and pain. These studies will be conducted in a research environment that features substantial expertise in behavioral neuroscience and neuropharmacology within a comprehensive physiology department and drug abuse center that will maximize the translational potential of these and future directions.