Abstract
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.
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Acknowledgements
This work was supported financially by Intramural Research Program, NIDA and DA11185 (GIE). We thank Nobuyuki Takahashi for excellent consultation; Hsin-Fei Liu, Nancy Goodman, and Steven Kinsey for technical assistance; and Linda Kazlo for assistance with the manuscript. We gratefully acknowledge animal care support from the Charles River/Triad animal care support section. Experiments were conducted under protocols approved by the NIDA Animal Care and Use Committee.
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Sora, I., Elmer, G., Funada, M. et al. μ Opiate Receptor Gene Dose Effects on Different Morphine Actions: Evidence for Differential in vivo μ Receptor Reserve. Neuropsychopharmacol 25, 41–54 (2001). https://doi.org/10.1016/S0893-133X(00)00252-9
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DOI: https://doi.org/10.1016/S0893-133X(00)00252-9
