PMID- 38145984 OWN - NLM STAT- Publisher LR - 20240108 IS - 1476-5578 (Electronic) IS - 1359-4184 (Linking) DP - 2023 Dec 25 TI - Unique pharmacodynamic properties and low abuse liability of the micro-opioid receptor ligand (S)-methadone. LID - 10.1038/s41380-023-02353-z [doi] AB - (R,S)-methadone ((R,S)-MTD) is a micro-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 Gal(1) receptor (Gal(1)R) 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-Gal(1)R heteromer, decreasing its abuse liability. CI - (c) 2023. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. FAU - Levinstein, Marjorie R AU - Levinstein MR AUID- ORCID: 0000-0003-4360-1503 AD - Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. FAU - De Oliveira, Paulo A AU - De Oliveira PA AD - Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. FAU - Casajuana-Martin, Nil AU - Casajuana-Martin N AUID- ORCID: 0000-0002-9007-274X AD - Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autonoma Barcelona, Bellaterra, 08193, Barcelona, Spain. FAU - Quiroz, Cesar AU - Quiroz C AD - Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. FAU - Budinich, Reece C AU - Budinich RC AD - Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. FAU - Rais, Rana AU - Rais R AD - Johns Hopkins Drug Discovery, Neurology and Pharmacology, Johns Hopkins School of Medicine, Baltimore, MD, 21205, USA. FAU - Rea, William AU - Rea W AD - Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. FAU - Ventriglia, Emilya N AU - Ventriglia EN AD - Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. FAU - Llopart, Natalia AU - Llopart N AUID- ORCID: 0000-0002-3127-2901 AD - Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institut de Biomedicina de la Universitat de Barcelona, 08028, Barcelona, Spain. FAU - Casado-Anguera, Veronica AU - Casado-Anguera V AD - Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institut de Biomedicina de la Universitat de Barcelona, 08028, Barcelona, Spain. FAU - Moreno, Estefania AU - Moreno E AUID- ORCID: 0000-0002-2491-5753 AD - Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institut de Biomedicina de la Universitat de Barcelona, 08028, Barcelona, Spain. FAU - Walther, Donna AU - Walther D AD - Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. FAU - Glatfelter, Grant C AU - Glatfelter GC AD - Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. FAU - Weinshenker, David AU - Weinshenker D AUID- ORCID: 0000-0002-3678-6215 AD - Department of Human Genetics, Emory University School of Medicine, Atlanta, GA, 30322, USA. FAU - Zarate, Carlos A Jr AU - Zarate CA Jr AD - Section on the Neurobiology and Treatment of Mood Disorders, National Institute of Mental Health Intramural Research Program, Bethesda, MD, 20892, USA. FAU - Casado, Vicent AU - Casado V AUID- ORCID: 0000-0002-1764-3825 AD - Laboratory of Molecular Neuropharmacology, Department of Biochemistry and Molecular Biomedicine, Faculty of Biology and Institut de Biomedicina de la Universitat de Barcelona, 08028, Barcelona, Spain. FAU - Baumann, Michael H AU - Baumann MH AD - Designer Drug Research Unit, Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore, MD, 21224, USA. FAU - Pardo, Leonardo AU - Pardo L AD - Laboratory of Computational Medicine, Biostatistics Unit, Faculty of Medicine, Universitat Autonoma Barcelona, Bellaterra, 08193, Barcelona, Spain. FAU - Ferre, Sergi AU - Ferre S AUID- ORCID: 0000-0002-1747-1779 AD - Integrative Neurobiology Section, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. sergi.ferre@nih.gov. FAU - Michaelides, Michael AU - Michaelides M AUID- ORCID: 0000-0003-0398-4917 AD - Biobehavioral Imaging and Molecular Neuropsychopharmacology Unit, National Institute on Drug Abuse Intramural Research Program, Baltimore, MD, 21224, USA. mike.michaelides@nih.gov. AD - Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA. mike.michaelides@nih.gov. LA - eng GR - ZIA DA000069/ImNIH/Intramural NIH HHS/United States PT - Journal Article DEP - 20231225 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 SB - IM UOF - Res Sq. 2023 Mar 23;:. PMID: 36993715 EDAT- 2023/12/26 00:42 MHDA- 2023/12/26 00:42 CRDT- 2023/12/25 23:13 PHST- 2023/06/30 00:00 [received] PHST- 2023/11/27 00:00 [accepted] PHST- 2023/11/20 00:00 [revised] PHST- 2023/12/26 00:42 [medline] PHST- 2023/12/26 00:42 [pubmed] PHST- 2023/12/25 23:13 [entrez] AID - 10.1038/s41380-023-02353-z [pii] AID - 10.1038/s41380-023-02353-z [doi] PST - aheadofprint SO - Mol Psychiatry. 2023 Dec 25. doi: 10.1038/s41380-023-02353-z.