期刊
JOURNAL OF NEUROSCIENCE
卷 31, 期 12, 页码 4434-4443出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.4874-10.2011
关键词
-
资金
- National Institutes of Health [DA023793, DA020972, DA08163, DA012864]
Chronic treatment with morphine results in a decrease in mu-opioid receptor sensitivity, an increase in acute desensitization, and a reduction in the recovery from acute desensitization in locus ceruleus neurons. With acute administration, morphine is unlike many other opioid agonists in that it does not mediate robust acute desensitization or induce receptor trafficking. This study compares mu-opioid receptor desensitization and trafficking in brain slices taken from rats treated for 6-7 d with a range of doses of morphine (60, 30, and 15 mg . kg(-1) . d(-1)) and methadone (60, 30, and 5 mg . kg(-1) . d(-1)) applied by subcutaneous implantation of osmotic mini-pumps. Mice were treated with 45 mg . kg(-1) . d(-1). In morphine-treated animals, recovery from acute [ Met](5) enkephalin-induced desensitization and receptor recycling was diminished. In contrast, recovery and recycling were unchanged in slices from methadone-treated animals. Remarkably the reduced recovery from desensitization and receptor recycling found in slices from morphine-treated animals were not observed in animals lacking beta-arrestin-2. Furthermore, pharmacological inhibition of G-protein receptor kinase 2 (GRK2), although not affecting the ability of [Met](5) enkephalin to induce desensitization, acutely reversed the delay in recovery from desensitization produced by chronic morphine treatment. These results characterize a previously unidentified function of the GRK/arrestin system in mediating opioid regulation in response to chronic morphine administration. They also suggest that the GRK/arrestin system, rather than serving as a primary mediator of acute desensitization, controls recovery from desensitization by regulating receptor reinsertion to the plasma membrane after chronic treatment with morphine. The sustained GRK/arrestin-dependent desensitization is another way in which morphine and methadone are distinguished.
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