title: Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism.
abstract: The OPRM1 A118G polymorphism is the most widely studied μ-opioid receptor (MOR) variant. Although its involvement in acute alcohol effects is well characterized, less is known about the extent to which it alters responses to opioids. Prior work has shown that both electrophysiological and analgesic responses to morphine but not to fentanyl are moderated by OPRM1 A118G variation, but the mechanism behind this dissociation is not known. Here we found that humanized mice carrying the 118GG allele (h/mOPRM1-118GG) were less sensitive than h/mOPRM1-118AA littermates to the rewarding effects of morphine and hydrocodone but not those of other opioids measured with intracranial self-stimulation. Reduced morphine reward in 118GG mice was associated with decreased dopamine release in the nucleus accumbens and reduced effects on GABA release in the ventral tegmental area that were not due to changes in drug potency or efficacy in vitro or receptor-binding affinity. Fewer MOR-binding sites were observed in h/mOPRM1-118GG mice, and pharmacological reduction of MOR availability unmasked genotypic differences in fentanyl sensitivity. These findings suggest that the OPRM1 A118G polymorphism decreases sensitivity to low-potency agonists by decreasing receptor reserve without significantly altering receptor function.
authors.affiliation: Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: J Elliott
authors.initials: JE
authors.lastname: Robinson
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Eyal
authors.initials: E
authors.lastname: Vardy
authors.affiliation: Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Jeffrey F
authors.initials: JF
authors.lastname: DiBerto
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse (NIDA), Baltimore, MD, USA.
authors.forename: Vladimir I
authors.initials: VI
authors.lastname: Chefer
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Kate L
authors.initials: KL
authors.lastname: White
authors.affiliation: Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Fish
authors.affiliation: Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Meng
authors.initials: M
authors.lastname: Chen
authors.affiliation: Intramural Research Program, National Institute on Drug Abuse (NIDA), Baltimore, MD, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Gigante
authors.affiliation: Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Krouse
authors.affiliation: Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Annika
authors.initials: A
authors.lastname: Thorsell
authors.affiliation: Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|NIMH Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.affiliation: Intramural Research Program, National Institute on Alcohol Abuse and Alcoholism (NIAAA), Bethesda, MD, USA.|Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.affiliation: Department of Neurology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Bowles Center for Alcohol Studies, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
authors.forename: C J
authors.initials: CJ
authors.lastname: Malanga
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D017450:Receptors, Opioid, mu / Q000235:genetics / Q000378:metabolism*; D012201:Reward; D012653:Self Stimulation; D046509:Tissue Culture Techniques; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; C485764:OPRM1 protein, human; C404943:Oprm protein, mouse; D017450:Receptors, Opioid, mu; D005680:gamma-Aminobutyric Acid; D004298:Dopamine