mu opiate receptor gene dose effects on different morphine actions: Evidence for differential in vivo mu receptor reserve

Homozygous transgenic knockout mice without mu -opioid receptors lack morph ine-induced antinociception, locomotion, tolerance, physical dependence, an d reward. mu receptors thus appear to play central roles in these morphine actions. Different levels of mu receptor expression are found in different humans and in different animal strains. In vitro studies indicate that some morphine responses persist after inactivation of as many as 90% of the ini tial mu receptor complement, while others are attenuated after inactivating many fewer receptors. Varying levels of mu receptor reserve could thus exi st in different mu -expressing neuronal populations in vivo. Heterozygous m u receptor knockout mice express half of wild-type mu receptor levels. Test s of morphine actions in these mice reveal evidence for differing mu recept or reserves in brain circuits that mediate distinct opiate effects. Heteroz ygotes display attenuated locomotion, reduced morphine self-administration, intact tolerance, rightward shifts in morphine lethality dose/effect relat ionships, and variable effects on place preference compared to wild-type mi ce. They demonstrate full physical dependence, as measured by naloxone-prec ipitated abstinence following five days of morphine administration. Neuroad aptive changes in sites other than mu receptors could be involved in some o f these results. Nevertheless, these data document substantial influences t hat individual differences in levels of mu receptor expression could exert on distinct opiate drug effects. They support the idea that functional mu r eceptor reserve differs among the diverse neuronal populations that mediate distinct properties of opiate drugs. [Neuropsychopharmacology 25:41-54, 20 01] (C) 2001 American College of Neuropsychopharmacology. Published by Else vier Science Inc.