A novel approach to treating opioid use disorders: Dual agonists of glucagon-like peptide-1 receptors and neuropeptide Y 2 receptors

• Published in: Neuroscience and biobehavioral reviews Vol. 131; p. 1169
• Main Authors: Merkel, Riley, Moreno, Amanda, Zhang, Yafang, Herman, Rachel, Ben Nathan, Jennifer, Zeb, Sana, Rahematpura, Suditi, Stecyk, Kamryn, Milliken, Brandon T, Hayes, Matthew R, Doyle, Robert P, Schmidt, Heath D
• Format: Journal Article
• Language: English
• Published: United States 01.12.2021
• Subjects: Animals; Fentanyl; Glucagon-Like Peptide-1 Receptor - agonists; Opioid-Related Disorders - drug therapy; Rats; Receptors, Neuropeptide Y - agonists; Drug self-administration; Relapse; GLP-1; Reinstatement; Opioid; Exendin-4; PYY(3-36)
• ISSN: 1873-7528
• DOI: 10.1016/j.neubiorev.2021.10.026

The widespread misuse of opioids and opioid use disorder (OUD) together constitute a major public health crisis in the United States. The greatest challenge for successfully treating OUD is preventing relapse. Unfortunately, there are few FDA-approved medications to treat OUD and, while effective, these pharmacotherapies are limited by high relapse rates. Thus, there is a critical need for conceptually new approaches to developing novel medications to treat OUD. Here, we review an emerging preclinical literature that suggests that glucagon-like peptide-1 receptor (GLP-1R) agonists could be re-purposed for treating OUD. Potential limitations of this approach are also discussed along with an alternative strategy that involves simultaneously targeting and activating GLP-1Rs and neuropeptide Y2 receptors (Y2Rs) in the brain using a novel monomeric dual agonist peptide. Recent studies indicate that this combinatorial pharmacotherapy approach attenuates voluntary fentanyl taking and seeking in rats without producing adverse effects associated with GLP-1R agonist monotherapy alone. While future studies are required to comprehensively determine the behavioral effects of GLP-1R agonists and dual agonists of GLP-1Rs and Y2Rs in rodent models of OUD, these provocative preclinical findings highlight a potential new GLP-1R-based approach to preventing relapse in humans with OUD.