Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence.
Morphine is a powerful pain reliever, but also a potent inducer of tolerance and dependence. The development of opiate tolerance occurs on continued use of the drug such that the amount of drug required to elicit pain relief must be increased to compensate for diminished responsiveness. In many systems, decreased responsiveness to agonists has been correlated with the desensitization of G-protein-coupled receptors. In vitro evidence indicates that this process involves phosphorylation of G-protein-coupled receptors and subsequent binding of regulatory proteins called beta-arrestins. Using a knockout mouse lacking beta-arrestin-2 (beta arr2-/-), we have assessed the contribution of desensitization of the mu-opioid receptor to the development of morphine antinociceptive tolerance and the subsequent onset of physical dependence. Here we show that in mice lacking beta-arrestin-2, desensitization of the mu-opioid receptor does not occur after chronic morphine treatment, and that these animals fail to develop antinociceptive tolerance. However, the deletion of beta-arrestin-2 does not prevent the chronic morphine-induced up-regulation of adenylyl cyclase activity, a cellular marker of dependence, and the mutant mice still become physically dependent on the drug.
Bohn
L M
LM
Howard Hughes Medical Institute Laboratories, Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710, USA.
Gainetdinov
R R
RR
Lin
F T
FT
Lefkowitz
R J
RJ
Caron
M G
MG
D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D019390:Arrestins / Q000502:physiology*; D001933:Brain Stem / Q000378:metabolism; D004343:Drug Implants; D004361:Drug Tolerance; D019204:GTP-Binding Proteins / Q000378:metabolism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008566:Membranes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009021:Morphine Dependence / Q000378:metabolism; D009154:Mutation; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins
D000701:Analgesics, Opioid; C000605258:Arrb2 protein, mouse; D019390:Arrestins; D004343:Drug Implants; D017450:Receptors, Opioid, mu; D000071560:beta-Arrestin 2; D000071557:beta-Arrestins; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009020:Morphine; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases