Unique pharmacodynamic properties and low abuse liability of the µ-opioid receptor ligand (S)-methadone.

ABSTRACT: (R,S)-methadone ((R,S)-MTD) is a µ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers. (S)-MTD is being developed as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. We compared the pharmacology of (R)-MTD and (S)-MTD and found they bind to MORs, but not NMDARs, and induce full analgesia. Unlike (R)-MTD, (S)-MTD was a weak reinforcer that failed to affect extracellular dopamine or induce locomotor stimulation. Furthermore, (S)-MTD antagonized motor and dopamine releasing effects of (R)-MTD. (S)-MTD acted as a partial agonist at MOR, with complete loss of efficacy at the MOR-galanin Gal₁ receptor (Gal₁R) heteromer, a key mediator of the dopaminergic effects of opioids. In sum, we report novel and unique ph

SUBMITTER: Levinstein MR 

PROVIDER: S-EPMC11221360 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature