A novel approach to treating opioid use disorders: Dual agonists of glucagon-like peptide-1 receptors and neuropeptide Y2 receptors

Neurosci Biobehav Rev. 2021 Dec;131:1169-1179. doi: 10.1016/j.neubiorev.2021.10.026. Epub 2021 Oct 29.


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.

Keywords: Drug self-administration; Exendin-4; GLP-1; Opioid; PYY(3-36); Reinstatement; Relapse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Fentanyl
  • Glucagon-Like Peptide-1 Receptor* / agonists
  • Opioid-Related Disorders* / drug therapy
  • Rats
  • Receptors, Neuropeptide Y / agonists*


  • Glucagon-Like Peptide-1 Receptor
  • Receptors, Neuropeptide Y
  • Fentanyl