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 toleranc e and dependence. The development of opiate tolerance occurs on continued u se of the drug such that the amount of drug required to elicit pain relief must be increased to compensate for diminished responsiveness(1-3). In many systems, decreased responsiveness to agonists has been correlated with the desensitization of G-protein-coupled receptors. In vitro evidence indicate s that this process involves phosphorylation of G-protein-coupled receptors and subsequent binding of regulatory proteins called beta -arrestins(4,5). 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 on set of physical dependence. Here we show that in mice lacking beta -arresti n-2, desensitization of the mu -opioid receptor does not occur after chroni c morphine treatment, and that these animals fail to develop antinociceptiv e tolerance. However, the deletion of beta -arrestin-2 does not prevent the chronic morphine-induced upregulation of adenylyl cyclase activity, a cell ular marker of dependence, and the mutant mice still become physically depe ndent on the drug.