The Mu‐Delta Opioid Receptor Heterodimer Promotes Acute and Chronic Morphine Induced Dependence/Withdrawal in Mice

Abstract

Opioid drugs like morphine are the gold standard for treating acute and chronic pain, but induce detrimental side effects such as tolerance and dependence. It has been suggested that the mu‐delta opioid receptor heterodimer (MDOR) transduces some of these side effects and that heterodimer targeted drugs could be a solution to weaken these side effects. We have thus created an MDOR selective antagonist called D24M. We evaluated D24M in vitro, and found a ~100 fold selectivity for the MDOR over the monomers. Similarly, we performed hot water tail‐flick experiments in mice in the presence of various doses of D24M against CYM51010 and Deltorphin‐2 (MDOR selective agonist), and DAMGO (MOR monomer selective agonist), and found that D24M potently (A50=2–7.8 nmol) blocked MDOR activity with no activity against the MOR monomer up to 10 nmol. To test the ability of D24M to lessen acute or chronic morphine‐induced dependence and withdrawal, we established acute (4 hr) and chronic (4 day) morphine dependence models, with 1 nmol D24M or vehicle injected 5 minutes prior to naloxone precipitation of withdrawal. We found that D24M strongly reduced jumping behavior in dependent mice in both the acutely and chronically models; further confirming that the MDOR promotes withdrawal behavior, and that D24M could possibly be a promising drug candidate for opioid dependence and withdrawal. These discoveries will further determine the role of the MDOR in vivo, and provide a novel tool that could greatly impact opioid heterodimer research.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.