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Science 286 (5449): 2495-2498

Copyright © 1999 by the American Association for the Advancement of Science

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}; or caron002{at}

ddagger    To whom requests for materials should be addressed.

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Receptor Endocytosis Counteracts the Development of Opioid Tolerance.
T. Koch, A. Widera, K. Bartzsch, S. Schulz, L.-O. Brandenburg, N. Wundrack, A. Beyer, G. Grecksch, and V. Hollt (2005)
Mol. Pharmacol. 67, 280-287
   Abstract »    Full Text »    PDF »
Protein Kinase C Activation Enhances Morphine-Induced Rapid Desensitization of {micro}-Opioid Receptors in Mature Rat Locus Ceruleus Neurons.
C. P. Bailey, E. Kelly, and G. Henderson (2004)
Mol. Pharmacol. 66, 1592-1598
   Abstract »    Full Text »    PDF »
Role of mPKCI, a Novel {micro}-Opioid Receptor Interactive Protein, in Receptor Desensitization, Phosphorylation, and Morphine-Induced Analgesia.
W. Guang, H. Wang, T. Su, I. B. Weinstein, and J. B. Wang (2004)
Mol. Pharmacol. 66, 1285-1292
   Abstract »    Full Text »    PDF »
Opioids As Modulators of Cell Death and Survival--Unraveling Mechanisms and Revealing New Indications.
I. Tegeder and G. Geisslinger (2004)
Pharmacol. Rev. 56, 351-369
   Abstract »    Full Text »    PDF »
Morphine induces terminal {mu}-opioid receptor desensitization by sustained phosphorylation of serine-375.
S. Schulz, D. Mayer, M. Pfeiffer, R. Stumm, T. Koch, and V. Hollt (2004)
EMBO J. 23, 3282-3289
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Relative Opioid Efficacy Is Determined by the Complements of the G Protein-Coupled Receptor Desensitization Machinery.
L. M. Bohn, L. A. Dykstra, R. J. Lefkowitz, M. G. Caron, and L. S. Barak (2004)
Mol. Pharmacol. 66, 106-112
   Abstract »    Full Text »    PDF »
Spinophilin Blocks Arrestin Actions in Vitro and in Vivo at G Protein-Coupled Receptors.
Q. Wang, J. Zhao, A. E. Brady, J. Feng, P. B. Allen, R. J. Lefkowitz, P. Greengard, and L. E. Limbird (2004)
Science 304, 1940-1944
   Abstract »    Full Text »    PDF »
Reduced GRK2 level in T cells potentiates chemotaxis and signaling in response to CCL4.
A. Vroon, C. J. Heijnen, M. S. Lombardi, P. M. Cobelens, F. Mayor Jr, M. G. Caron, and A. Kavelaars (2004)
J. Leukoc. Biol. 75, 901-909
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Prolonged Kappa Opioid Receptor Phosphorylation Mediated by G-protein Receptor Kinase Underlies Sustained Analgesic Tolerance.
J. P. McLaughlin, L. C. Myers, P. E. Zarek, M. G. Caron, R. J. Lefkowitz, T. A. Czyzyk, J. E. Pintar, and C. Chavkin (2004)
J. Biol. Chem. 279, 1810-1818
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The Unique Amino-terminal Region of the PDE4D5 cAMP Phosphodiesterase Isoform Confers Preferential Interaction with {beta}-Arrestins.
G. B. Bolger, A. McCahill, E. Huston, Y.-F. Cheung, T. McSorley, G. S. Baillie, and M. D. Houslay (2003)
J. Biol. Chem. 278, 49230-49238
   Abstract »    Full Text »    PDF »
Enhanced Rewarding Properties of Morphine, but not Cocaine, in {beta}arrestin-2 Knock-Out Mice.
L. M. Bohn, R. R. Gainetdinov, T. D. Sotnikova, I. O. Medvedev, R. J. Lefkowitz, L. A. Dykstra, and M. G. Caron (2003)
J. Neurosci. 23, 10265-10273
   Abstract »    Full Text »    PDF »
The Adaptor Protein {beta}-Arrestin2 Enhances Endocytosis of the Low Density Lipoprotein Receptor.
J.-H. Wu, K. Peppel, C. D. Nelson, F.-T. Lin, T. A. Kohout, W. E. Miller, S. T. Exum, and N. J. Freedman (2003)
J. Biol. Chem. 278, 44238-44245
   Abstract »    Full Text »    PDF »
{beta}-Arrestin 2 Mediates Endocytosis of Type III TGF-{beta} Receptor and Down-Regulation of Its Signaling.
W. Chen, K. C. Kirkbride, T. How, C. D. Nelson, J. Mo, J. P. Frederick, X.-F. Wang, R. J. Lefkowitz, and G. C. Blobe (2003)
Science 301, 1394-1397
   Abstract »    Full Text »    PDF »
G-protein-coupled Receptor (GPCR) Kinase Phosphorylation and {beta}-Arrestin Recruitment Regulate the Constitutive Signaling Activity of the Human Cytomegalovirus US28 GPCR.
W. E. Miller, D. A. Houtz, C. D. Nelson, P. E. Kolattukudy, and R. J. Lefkowitz (2003)
J. Biol. Chem. 278, 21663-21671
   Abstract »    Full Text »    PDF »

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