Acute glucagon-like peptide-1 receptor agonist, semaglutide, attenuates cue-, drug-, and stress-induced fentanyl seeking in male Sprague-Dawley rats.
Semaglutide showed potential in preventing fentanyl seeking behavior in rats, but further research is needed to determine its relevance for human opioid use disorder treatment.
Where it sits
this study against the rest of the exenatide corpusSummary and findings
This study investigated the effects of semaglutide on fentanyl seeking behavior in male Sprague-Dawley rats. Semaglutide was administered subcutaneously at doses of 0.026, 0.056, and 0.078 mg/kg. Results indicated that all doses prevented drug- and stress-induced reinstatement of fentanyl seeking.
Abstract
Opioid overdose deaths continue to be a significant public health problem worldwide, with fentanyl, the primary driver of these losses of life. Indeed, in the USA, overdose deaths continue despite the availability of three food and drug administration-approved medications for the treatment of opioid use disorder (OUD) due to minimal access to these medications and to stigma. Fortunately, a growing preclinical and clinical literature suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists may serve as new treatments for OUD. Exendin-4/exenatide and liraglutide have been found to reduce opioid intake, cravings, and cue-, drug-, and stress-induced opioid seeking. While these are important findings, exenatide has a higher risk of gastrointestinal distress and, due to its short half-life, requires multiple daily injections for treatment. Liraglutide has a longer half-life, is less likely than exenatide to cause gastrointestinal distress, but still requires daily injections, which many patients find objectionable. Semaglutide, on the other hand, is a GLP-1R agonist with a longer half-life that requires once weekly injections in humans. Some evidence suggests that semaglutide can reduce responding for alcohol, but it is not known whether it can reduce responding for opioids. Here we test whether acute treatment with semaglutide at 0.026, 0.056, and 0.078 mg/kg administered subcutaneously can reduce cue-, drug-, and stress-induced fentanyl seeking in rats. Results show that all doses of semaglutide fully prevented drug- and stress-induced reinstatement of fentanyl seeking elicited by an i.v. infusion of 1.85 µg/kg fentanyl or the i.p. administration of 0.5 mg/kg yohimbine, respectively, while the mid (0.056 mg/kg) and higher doses (0.078 mg/kg) most effectively reduced cue-induced fentanyl seeking. These findings suggest that semaglutide may serve as an additional nonopioid GLP-1R agonist for the treatment of OUD.
Background
This paper addresses the potential of glucagon-like peptide-1 receptor (GLP-1R) agonists, specifically semaglutide, in reducing opioid seeking behavior. Previous studies indicated that GLP-1R agonists like exenatide and liraglutide can reduce opioid intake and cravings. The significance of this study lies in exploring a new GLP-1R agonist, semaglutide, which has a longer half-life and may offer a different administration schedule compared to existing treatments.
Methods
The study utilized a preclinical design involving male Sprague-Dawley rats. The sample size is not reported in the abstract. Semaglutide was administered subcutaneously at doses of 0.026, 0.056, and 0.078 mg/kg. The primary outcome measures included cue-, drug-, and stress-induced reinstatement of fentanyl seeking, assessed after administration of fentanyl and yohimbine.
Results
All doses of semaglutide fully prevented drug- and stress-induced reinstatement of fentanyl seeking. The mid (0.056 mg/kg) and higher doses (0.078 mg/kg) were particularly effective in reducing cue-induced fentanyl seeking. Specific p-values and confidence intervals are not reported in the abstract.
Interpretation
The findings suggest that semaglutide may have potential as a nonopioid treatment for opioid use disorder, similar to other GLP-1R agonists. However, the effect sizes and clinical significance remain to be established in human trials. The limitations of using rodent models and the absence of long-term follow-up data may confound the applicability of these results to human populations.
Key findings
- All doses of semaglutide fully prevented drug-induced reinstatement of fentanyl seeking elicited by an i.v. infusion of 1.85 µg/kg fentanyl.
- All doses of semaglutide fully prevented stress-induced reinstatement of fentanyl seeking elicited by an i.p. administration of 0.5 mg/kg yohimbine.
- The mid (0.056 mg/kg) and higher doses (0.078 mg/kg) most effectively reduced cue-induced fentanyl seeking.
Limitations
- Rodent model, results may not translate to humans.
- Sample size not reported.
- Preclinical study, requires human trials for validation.