Walther, DonnaGlatfelter, Grant C.Weinshenker, DavidZarate, Carlos A.Casadó, VicentBaumann, Michael H.Pardo, LeonardoFerré, SergiMichaelides, MichaelLevinstein, MarjorieDe Oliveira, Paulo A.Casajuana-Martin, NilQuiroz, CésarBudinich, Reece C.Rais, RanaRea, WilliamVentriglia, EmilyaLlopart, NatàliaCasadó Anguera, VerònicaMoreno Guillén, Estefanía2026-01-232026-01-232024-03-011359-4184https://hdl.handle.net/2445/226055(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 pharmacodynamic properties of (S)-MTD that are relevant to its potential mechanism of action and therapeutic use. One-sentence summary: (S)-MTD, like (R)-MTD, binds to and activates MORs in vitro, but (S)-MTD antagonizes the MOR-Gal1R heteromer, decreasing its abuse liability.9 p.application/pdfeng(c) Levinstein, MR et al., 2024OpiacisReceptors de neurotransmissorsOpioidsNeurotransmitter receptorsinfo:eu-repo/semantics/article7420882026-01-23info:eu-repo/semantics/openAccess