PF5190457 reduces fentanyl intake and seeking with a low risk pharmacological profile in male rats

The opioid epidemic remains a persistent public health challenge in the United States, leaving many people affected by or vulnerable to opioid use disorder (OUD). Although US Food and Drug Administration-approved medications for OUD improve the odds of recovery and reduce mortality, relapse rates remain high and access, adherence, and individual response variabilities limit their overall impact. The ongoing burden of OUD therefore underscores the need to develop additional therapeutics that target complementary biological mechanisms and support long-term recovery. One strategy of interest is to delineate the biological overlap between OUD and other motivated behaviors, particularly the neurobiology underlying appetitive and reward-driven processes. The orexigenic peptide hormone ghrelin, often referred to as the "hunger hormone," regulates energy homeostasis, hedonic feeding, and reward sensitivity by binding to the growth hormone secretagogue receptor 1α (GHS1αR), a receptor expressed in mesolimbic circuits implicated in addiction. In the present study, we used the inverse agonist/antagonist PF5190457 to assess the impact of full GHS1αR blockade on fentanyl-mediated behaviors in preclinical models. We found that PF5190457 significantly reduced fentanyl self-administration and attenuated drug-seeking during cue tests while maintaining a favorable pharmacological and safety profile in risk assessment assays, including measures of withdrawal and respiratory depression. Collectively, these findings demonstrate a functional role for ghrelin-GHS1αR signaling in the reinforcing effects of fentanyl and positions GHS1αR inverse agonism as a promising, mechanistically novel therapeutic strategy for OUD treatment. SIGNIFICANCE STATEMENT: The present work demonstrates that the growth hormone secretagogue receptor 1α (GHS1αR) inverse agonist/antagonist PF5190457 reduces fentanyl self-administration and drug-seeking while maintaining a favorable safety profile in male rats, supporting ghrelin-GHS1αR modulation as a promising therapeutic strategy for opioid use disorder.