Unique pharmacodynamic properties and low abuse liability of the μ-opioid receptor ligand (S)-methadone
Michaelides, Michael (NIH)
Levinstein, Marjorie (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
De Oliveira, Paulo (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Casajuana-Martin, Nil (Universitat Autònoma de Barcelona)
Quiroz, Cesar (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Budinich, Reece (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Rais, Rana (Johns Hopkins School of Medicine)
Rea, William (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Ventriglia, Emilya (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Llopart, Natàlia (Universitat de Barcelona)
Casadó-Anguera, Verònica (Universitat de Barcelona)
Moreno, Estefanía (University of Barcelona. Department of Biochemistry and Molecular Biomedicine)
Walther, Donna (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Glatfelter, Grant (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Weinshenker, David
Zarate, Carlos (NIMH)
Casadó, Vicent (Universitat de Barcelona)
Baumann, Michael (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))
Pardo Carrasco, Leonardo (Universitat Autònoma de Barcelona)
Ferré, Sergi (National Institute on Drug Abuse (Baltimore, Estats Units d'Amèrica))

Date:	2023
Abstract:	(R,S)-methadone ((R,S)-MTD) is a racemic μ-opioid receptor (MOR) agonist comprised of (R)-MTD and (S)-MTD enantiomers used for the treatment of opioid use disorder (OUD) and pain. (R)-MTD is used as an OUD treatment, has high MOR potency, and is believed to mediate (R,S)-MTD's therapeutic efficacy. (S)-MTD is in clinical development as an antidepressant and is considered an N-methyl-D-aspartate receptor (NMDAR) antagonist. In opposition to this purported mechanism of action, we found that (S)-MTD does not occupy NMDARs in vivo in rats. Instead, (S)-MTD produced MOR occupancy and induced analgesia with similar efficacy as (R)-MTD. Unlike (R)-MTD, (S)-MTD was not self-administered and failed to increase locomotion or extracellular dopamine levels indicating low abuse liability. Moreover, (S)-MTD antagonized the effects of (R)-MTD in vivo and exhibited unique pharmacodynamic properties, distinct from those of (R)-MTD. Specifically, (S)-MTD acted as a MOR partial agonist with a specific loss of efficacy at the MOR-galanin 1 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, as well as those of (R,S)-MTD.
Grants:	Agencia Estatal de Investigación PID2022-140912OB-I00 Agencia Estatal de Investigación FJC2019-041020-I Agència de Gestió d'Ajuts Universitaris i de Recerca 2021/SGR-00230
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Prepublicació ; recerca ; Versió de l'autor
Subject:	Opioid ; Computational model ; NMDAR

DOI: 10.21203/rs.3.rs-2644719/v1
PMID: 36993715

21 p, 2.0 MB

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Research literature > Preprints