Semaglutide acutely attenuates cue-, drug-, and stress-induced fentanyl seeking in male rats

The global opioid overdose crisis, primarily driven by fentanyl, remains a critical public health challenge. Despite the availability of three FDA-approved medications for Opioid Use Disorder (OUD), treatment access and stigma limit their impact. Current GLP-1R agonists like exenatide and liraglutide show promise in reducing opioid intake and seeking, but their short half-lives necessitate daily injections, which can hinder patient adherence. Semaglutide, a longer-acting GLP-1R agonist, offers a potential solution due to its once-weekly dosing in humans, making it a compelling candidate for OUD treatment.

Researchers investigated whether acute semaglutide could reduce fentanyl seeking in male Sprague-Dawley rats. Animals were administered 0.026, 0.056, or 0.078 mg/kg semaglutide subcutaneously (SC). The study assessed three types of fentanyl seeking: cue-induced, drug-induced (elicited by an i.v. infusion of 1.85 µg/kg fentanyl), and stress-induced (elicited by i.p. administration of 0.5 mg/kg yohimbine). The primary endpoint was the attenuation of these seeking behaviors, compared to control conditions.

Acute semaglutide treatment demonstrated significant efficacy in reducing fentanyl seeking across multiple paradigms. All tested doses of semaglutide (0.026, 0.056, and 0.078 mg/kg) fully prevented both drug-induced and stress-induced reinstatement of fentanyl seeking. These effects were observed when seeking was elicited by an i.v. infusion of 1.85 µg/kg fentanyl or i.p. administration of 0.5 mg/kg yohimbine, respectively. For cue-induced fentanyl seeking, the mid (0.056 mg/kg) and higher doses (0.078 mg/kg) of semaglutide were most effective in reducing the behavior. These findings highlight semaglutide's broad potential in mitigating various triggers for opioid relapse. The mechanism likely involves the GLP-1R pathway, which has been implicated in reward and addiction circuits. This preclinical evidence strongly supports further investigation into semaglutide for OUD.

All doses of semaglutide fully prevented drug- and stress-induced reinstatement of fentanyl seeking, while mid and higher doses most effectively reduced cue-induced seeking.