Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism

被引:0
作者
J Elliott Robinson
Eyal Vardy
Jeffrey F DiBerto
Vladimir I Chefer
Kate L White
Eric W Fish
Meng Chen
Eduardo Gigante
Michael C Krouse
Hui Sun
Annika Thorsell
Bryan L Roth
Markus Heilig
C J Malanga
机构
[1] School of Medicine,Department of Neurology
[2] University of North Carolina at Chapel Hill,Department of Pharmacology
[3] Bowles Center for Alcohol Studies,Department of Clinical and Experimental Medicine
[4] School of Medicine,undefined
[5] University of North Carolina at Chapel Hill,undefined
[6] School of Medicine,undefined
[7] University of North Carolina at Chapel Hill,undefined
[8] Intramural Research Program,undefined
[9] National Institute on Drug Abuse (NIDA),undefined
[10] Intramural Research Program,undefined
[11] National Institute on Alcohol Abuse and Alcoholism (NIAAA),undefined
[12] Linköping University,undefined
[13] NIMH Psychoactive Drug Screening Program (PDSP),undefined
[14] University of North Carolina at Chapel Hill,undefined
来源
Neuropsychopharmacology | 2015年 / 40卷
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摘要
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.
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页码:2614 / 2622
页数:8
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