Lm. Bohn et al., mu-Opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence, NATURE, 408(6813), 2000, pp. 720-723
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.