PROJECT SUMMARY The opioid crisis has spawned a myriad of health consequences, including increased incidence of opioid use disorder (OUD), a condition manifested by escalating physical and psychological impairments. Medication- assisted treatment (MAT) aids in reducing mortality, opioid withdrawal, intake and opioid-seeking behaviors, thus substantially improving the odds of successful recovery from OUD, particularly when coupled with psychosocial interventions. Current opioid-based MAT (i.e., buprenorphine) is a leading adjunct in the proper management of OUD patients, however there is a need to increase the armamentarium of therapeutics for OUD. The “non- classical” nociceptin receptor (NOPr) binds the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ), named for its efficacy to evoke nociception. Robust evidence supports the role of the N/OFQ-NOPr axis in the rewarding effects of alcohol and the therapeutic potential of NOPr ligands in alcohol use disorder. While less is established regarding this system in OUD, published literature implicates NOPr function in the regulation of the rewarding and motivational effects of opioids. Building on the premise that brain N/OFQ-NOPr axis is involved in OUD-related behaviors, we have partnered with BlackThorn Therapeutics to assess their novel and selective NOPr antagonist BTRX-246040 as a potential OUD therapeutic. In this UG3, we will assess BTRX-246040 to block oxycodone intake without abuse liability and to suppress oxycodone withdrawal and relapse-like behaviors in male and female rats. We will also determine drug metabolism and pharmacokinetics interactions (DMPK) between oxycodone and BTRX-246040 and brain penetrability in male and female rats. With achievement of the UG3 milestones, we will conduct a Phase 1 clinical trial in non-treatment seeking OUD participants in the UH3. Relative to placebo, we will ascertain the safety and tolerability of BTRX-246040 following oral oxycodone, the DMPK profile of oral oxycodone following BTRX-246040, and efficacy to suppress opioid craving and drug-liking in OUD participants. The second goal of the UH3 phase is to develop the preclinical data to support the prospect that BTRX-246040 may serve as an adjuvant to buprenorphine MAT. These investigations with the NOPr antagonist BTRX-246040 in the UG3/UH3 will advance the prospects to validate a novel medication for OUD.