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Science 24 December 1999:
Vol. 286. no. 5449, pp. 2495 - 2498
DOI: 10.1126/science.286.5449.2495
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Reports

Enhanced Morphine Analgesia in Mice Lacking beta -Arrestin 2 

Laura M. Bohn, 1* Robert J. Lefkowitz, 2dagger ddagger Raul R. Gainetdinov, 1 Karsten Peppel, 2 Marc G. Caron, 1dagger Fang-Tsyr Lin 2*

The ability of morphine to alleviate pain is mediated through a heterotrimeric guanine nucleotide binding protein (G protein)-coupled heptahelical receptor (GPCR), the µ opioid receptor (µOR). The efficiency of GPCR signaling is tightly regulated and ultimately limited by the coordinated phosphorylation of the receptors by specific GPCR kinases and the subsequent interaction of the phosphorylated receptors with beta -arrestin 1 and beta -arrestin 2. Functional deletion of the beta -arrestin 2 gene in mice resulted in remarkable potentiation and prolongation of the analgesic effect of morphine, suggesting that µOR desensitization was impaired. These results provide evidence in vivo for the physiological importance of beta -arrestin 2 in regulating the function of a specific GPCR, the µOR. Moreover, they suggest that inhibition of beta -arrestin 2 function might lead to enhanced analgesic effectiveness of morphine and provide potential new avenues for the study and treatment of pain, narcotic tolerance, and dependence.

1 Howard Hughes Medical Institute Laboratories, Departments of Cell Biology and Medicine,
2 Howard Hughes Medical Institute Laboratories, Departments of Biochemistry and Medicine, Duke University Medical Center, Durham, NC 27710, USA.
*   These authors contributed equally to this report.

dagger    To whom correspondence should be addressed. E-mail: lefko001{at}receptor-biol.duke.edu; or caron002{at}mc.duke.edu

ddagger    To whom requests for materials should be addressed.

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