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The Journal of Neuroscience, May 15, 2003, 23(10):4324-4332

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Morphine Acutely Regulates Opioid Receptor Trafficking Selectively in Dendrites of Nucleus Accumbens Neurons

Helena Haberstock-Debic,¹ Marc Wein,^1,2 Michel Barrot,^3,6 Eric E. O. Colago,⁴ Zia Rahman,³ Rachael L. Neve,⁵ Virginia M. Pickel,⁴ Eric J. Nestler,³ Mark von Zastrow,¹ and Adena L. Svingos⁴

¹Departments of Psychiatry and Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, California 94143-2140, ²Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut 06510, ³Department of Psychiatry and Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas 75390, ⁴Department of Neurology and Neuroscience, Weill Medical College of Cornell University, New York, New York 10021, ⁵Department of Neuroscience, McLean Hospital, Belmont, Massachusetts 02178, and ⁶Unité Mixte de Recherche, 7519 Centre National de la Recherche Scientifique/University Louis Pasteur, 67084 Strasbourg, France

Morphine stimulates the internalization of µ-opioid receptors (MORs) in transfected cell models to a lesser degree than opioid peptides and other analgesic drugs, such as methadone, and previous studies have reported that morphine does not produce a detectable redistribution of MORs in neural tissue after either acute or chronic administration. Nevertheless, morphine produces profound physiological effects, raising the question of whether receptor trafficking plays any role in the in vivo actions of morphine. We investigated the effects of opiate drugs on recombinant and native opioid receptors in the nucleus accumbens, which plays an important role in mediating the behavioral effects of opiate drugs. Morphine and methadone differed in their effects on the internalization of epitope-tagged MORs in cell bodies, introduced by viral gene transfer and imaged by fluorescence microscopy. A mutation of the cytoplasmic tail that confers morphine-induced internalization in cultured cells had a similar effect on receptor trafficking in nucleus accumbens cell bodies. Surprisingly, in contrast to its failure to affect MOR distribution detectably in cell bodies, acute morphine administration produced a pronounced change in MOR distribution visualized in the processes of the same neurons. A similar effect of acute morphine administration was observed for endogenously expressed MORs by immunoelectron microscopy; the acute administration of morphine increased the density of MORs associated with internal membrane structures specifically in dendrites. These results provide the first evidence that morphine regulates the distribution of MORs in neuronal processes, suggesting that "compartment-selective" membrane trafficking represents a previously unanticipated type of opioid receptor regulation contributing to the in vivo effects of opiate drugs on a physiologically relevant population of CNS neurons.

Key words: opiate; drug addiction; receptor trafficking; striatum; acute morphine administration; dendrite

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Received Dec. 11, 2002; revised Feb. 11, 2003; accepted Feb. 11, 2003.

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