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Mu-opioid receptor desensitization by beta-arrestin-2 determines morphine tolerance but not dependence 总被引:19,自引:0,他引:19
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. 相似文献
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Direct generation of functional dopaminergic neurons from mouse and human fibroblasts 总被引:2,自引:0,他引:2
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Zhang X Beaulieu JM Gainetdinov RR Caron MG 《Cellular and molecular life sciences : CMLS》2006,63(1):6-11
Many neuropsychiatric disorders are considered to be related to the dysregulation of brain serotonergic neurotransmission.
Tryptophan hydroxylase-2 (TPH2) is the neuronal-specific enzyme that controls brain serotonin synthesis. There is growing
genetic evidence for the possible involvement of TPH2 in serotonin-related neuropsychiatric disorders; however, the degree of genetic variation in TPH2 and, in particular, its possible functional consequences remain unknown. In this short review, we will summarize some recent
findings with respect to the functional analysis of TPH2.
Received 12 September 2005; received after revision 25 October 2005; accepted 31 October 2005 相似文献
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