期刊
JOURNAL OF NEUROSCIENCE
卷 31, 期 19, 页码 7122-7130出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.5999-10.2011
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-
资金
- National Health and Medical Research Council of Australia [351446, 511914]
Chronic morphine treatment produces behavioral and cellular opioid tolerance that has been proposed to be caused by attenuated mu-opioid receptor (MOR) recovery from desensitization (resensitization). The process of MOR resensitization is thought to require beta arrestin-2 (beta arr-2)dependent trafficking of desensitized receptors to endosomal compartments, followed by recycling of resensitized receptors back to the plasma membrane. However, there is little direct evidence for this, particularly in native neurons. This study used whole-cell patch-clamp recording in locus ceruleus (LC) neurons from wild-type (w.t.) and beta arr-2 knock-out (k.o.) mice to examine whether beta arr-2/dynamin-dependent trafficking is required for MOR resensitization in neurons from opioid-naive and morphine-treated mice. Surprisingly, recovery of MOR from acute desensitization in LC neurons does not require beta arr-2- or dynamin-dependent trafficking. To the contrary, MOR resensitization was accelerated by disruption of either beta arr-2 or dynamin function. Chronic morphine treatment caused cellular MOR tolerance and concurrently impaired MOR resensitization in neurons from w.t. mice, as expected from previous studies, but neither occurred in neurons from beta arr-2 k.o. mice. Moreover, the impairment of MOR resensitization caused by chronic morphine was reversed in w.t. neurons when G-protein-coupled receptor kinase-2 (GRK2) or dynamin function was disrupted. Together, these results establish that beta arr-2/dynamin-dependent receptor regulation is not required for MOR resensitization in LC neurons. Furthermore, chronic morphine treatment modifies GRK2-beta arr-2-dynamin-dependent MOR trafficking to impair receptor resensitization, thereby contributing to opioid tolerance in LC neurons by reducing the number of functional receptors on the surface membrane.
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