Study Author Marjorie Levinstein
Featured Paper of the Month – June 2024
Published in Molecular Psychiatry by Marjorie Levinstein and Michael Michaelides, et al. of the NIDA IRP Biobehavioral Imaging and Molecular Neuropsychopharmacology Section.
Summary
In this article we performed an in depth in vivo, in vitro, and in silico analysis of (R,S)-methadone and its enantiomers. (S)-methadone is currently in phase III trials as an antidepressant and is frequently referred to as an N-methyl-D-aspartate receptor (NMDAR) antagonist, like ketamine. Here we show that (S)-methadone, like (R)-methadone and (R,S)-methadone is an agonist at the mu opioid receptor (MOR) and does not bind to NMDARs at physiologically relevant concentrations. We also show that while (S)-methadone produces full analgesia like other opioids, it has very low abuse liability. We find that (S)-methadone generally acts as an agonist at MOR, but it acts as an antagonist at the MOR-galanin1 (Gal1) receptor heteromers of the ventral tegmental area and prevents opioid-induced mesolimbic dopamine release. We also used modeling to derive a potential mechanism to explain this functional change.
Publication Information
Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone Journal Article
In: Mol Psychiatry, 2023, ISSN: 1476-5578.
