Receptor Reserve Moderates Mesolimbic Responses to Opioids in a Humanized Mouse Model of the OPRM1 A118G Polymorphism
2015 (English)In: Neuropsychopharmacology, ISSN 0893-133X, E-ISSN 1740-634X, Vol. 40, no 11, 2614-2622 p.Article in journal (Refereed) Published
The OPRM1 A118G polymorphism is the most widely studied mu-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.
Place, publisher, year, edition, pages
NATURE PUBLISHING GROUP , 2015. Vol. 40, no 11, 2614-2622 p.
IdentifiersURN: urn:nbn:se:liu:diva-121737DOI: 10.1038/npp.2015.109ISI: 000361138300014PubMedID: 25881115OAI: oai:DiVA.org:liu-121737DiVA: diva2:859364
Funding Agencies|National Institute on Alcohol Abuse and Alcoholism [F30 AA021312, R01 AA018335]; National Institute on Drug Abuse [R01 DA017204]; Swedish Research Council [2010-3219]; intramural programs of the National Institute on Drug Abuse; NIH; Dai Nippon Sumitomo; Merck; Asubio Pharmaceuticals2015-10-062015-10-052016-01-21