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The Journal of Neuroscience, August 24, 2005, 25(34):7847-7857; doi:10.1523/JNEUROSCI.5045-04.2005

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Cellular/Molecular
Morphine Promotes Rapid, Arrestin-Dependent Endocytosis of µ-Opioid Receptors in Striatal Neurons

Helena Haberstock-Debic, Kyung-Ah Kim, Y. Joy Yu, and Mark von Zastrow

Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143

Morphine activates µ-opioid receptors (MORs) without promoting their rapid endocytosis in a number of cell types. A previous study suggested that morphine can drive rapid redistribution of MORs in the nucleus accumbens, but it was not possible in this in vivo study to identify a specific membrane trafficking pathway affected by morphine, to exclude possible indirect actions of morphine via opiate-regulated neural circuitry, or to define the mechanism of this morphine-dependent regulation. In the present study, we addressed these questions using dissociated primary cultures of rat striatal neurons as a model system. Morphine promoted a rapid redistribution of both endogenous and recombinant MORs within 30 min after drug addition to the culture medium. This effect was mediated by rapid endocytosis and occurred in a cell-autonomous manner, as indicated by its detection in cells plated at low density and in cultures in which depolarization was blocked by tetrodotoxin. Morphine-induced endocytosis of MORs was quantitatively similar to that induced by the enkephalin analog D-Ala2-N-Me-Phe4-Glycol5-enkephalin, and endocytosis induced by both ligands was inhibited by a dominant-negative mutant version of arrestin-3 ({beta}-arrestin-2). These results extend previous in vivo results and indicate that morphine is indeed capable of driving rapid endocytosis of µ-opioid receptors in an important subset of opiate-responsive CNS neurons. They also suggest a cellular mechanism by which {beta}-arrestins may modulate the physiological effects of morphine in vivo.

Key words: opiate; receptor trafficking; striatal neurons; acute morphine; endocytosis; {beta}-arrestin-2

Received Dec 10, 2004; revised July 1, 2005; accepted July 18, 2005.




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