Project Summary Opioids are powerful analgesics clinically used in treatment of chronic pain; they are also rewarding, and thus have high risk for abuse and dependence. Up to 25% of all patients receiving long-term opioid therapy struggle with opioid addiction, which is especially concerning considering that more than 191 million prescriptions for opioids were dispensed to patients in 2017 leading to the current opioid crisis. This has led to the search of novel strategies/therapeutic targets to treat pain. Hypothalamic neuropeptide receptors have emerged as potential targets for development of therapeutics for the treatment of substance use disorders. With the intent of identifying additional neuropeptide receptor systems, we recently deorphanized the hypothalamic receptor GPR83 as a receptor for an abundant neuropeptide, PEN. GPR83 is expressed in the reward centers of the brain. Also, local knock-down of GPR83 leads to attenuation of the rewarding effects of morphine making GPR83 a potential target for the development of novel therapeutics. The studies in this application are to characterize a recently identified small molecule antagonist targeting GPR83 with the intent of identifying drugs for the treatment of substance use disorders. These studies are highly significant since they are likely to open novel therapeutic possibilities for the treatment of addiction.