μ Opiate receptor gene dose effects on different morphine actions: Evidence for differential in vivo μ receptor reserve

Homozygous transgenic knockout mice without μ-opioid receptors lack morphine-induced antinociception, locomotion, tolerance, physical dependence, and reward. μ receptors thus appear to play central roles in these morphine actions. Different levels of μ 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 initial μ receptor complement, while others are attenuated after inactivating many fewer receptors. Varying levels of μ receptor reserve could thus exist in different μ-expressing neuronal populations in vivo. Heterozygous μ receptor knockout mice express half of wild-type μ receptor levels. Tests of morphine actions in these mice reveal evidence for differing μ receptor reserves in brain circuits that mediate distinct opiate effects. Heterozygotes display attenuated locomotion, reduced morphine self-administration, intact tolerance, rightward shifts in morphine lethality dose/effect relationships, and variable effects on place preference compared to wild-type mice. They demonstrate full physical dependence, as measured by naloxone-precipitated abstinence following five days of morphine administration. Neuroadaptive changes in sites other than μ receptors could be involved in some of these results. Nevertheless, these data document substantial influences that individual differences in levels of μ receptor expression could exert on distinct opiate drug effects. They support the idea that functional μ receptor reserve differs among the diverse neuronal populations that mediate distinct properties of opiate drugs.