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The Journal of Neuroscience, June 15, 2003, 23(12):4888-4898

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Regulation of -Opioid Receptor Trafficking via µ-Opioid Receptor Stimulation: Evidence from µ-Opioid Receptor Knock-Out Mice

Anne Morinville,^1,2 Catherine M. Cahill,² M. James Esdaile,² Haneen Aibak,² Brian Collier,¹ Brigitte L. Kieffer,³ and Alain Beaudet²

¹Department of Pharmacology and Therapeutics, McGill University, Montréal, Québec, Canada H3G 1Y6, ²Montréal Neurological Institute, McGill University, Montréal, Québec, Canada H3A 2B4, and ³Institute of Genetics and of Molecular and Cellular Biology, National Center of Scientific Research/National Institute of Health and of Medical Research, University Louis Pasteur, 67404 Illkirch, France

We recently demonstrated that prolonged treatment with morphine increases the antinociceptive potency of the -opioid receptor (OR) agonist deltorphin and promotes cell surface targeting of ORs in neurons of the dorsal horn of the rat spinal cord (Cahill et al., 2001b). In the present study we examined whether these effects were mediated selectively via µOR. Using the same intermittent treatment regimen as for morphine, we found that methadone and etorphine, but not fentanyl, enhanced [D-Ala²]-deltorphin-mediated antinociception. However, continuous delivery of fentanyl for 48 hr resulted in augmented OR-mediated antinociception when compared with saline-infused animals. Time course studies confirmed that a 48 hr treatment with morphine was necessary for the establishment of enhanced OR-mediated antinociception. The observed increases in OR agonist potency and OR plasma membrane density were reversed fully 48 hr after discontinuation of morphine injections. Wild-type C57BL/6 mice pretreated with morphine for 48 hr similarly displayed enhanced OR-mediated antinociception in a tonic pain paradigm. Accordingly, the percentage of plasma membrane-associated OR in the dorsal horn of the spinal cord, as assessed by immunogold electron microscopy, increased from 6.6% in naive to 12.4% in morphine-treated mice. In contrast, morphine treatment of µOR gene knock-out (KO) mice did not produce any change in OR plasma membrane density. These results demonstrate that selective activation of µOR is critical for morphine-induced targeting of OR to neuronal membranes, but not for basal targeting of this receptor to the cell surface.

Key words: opiate; targeting; analgesia; narcotic; subcellular localization; electron microscopy

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Received Dec. 10, 2002; revised Apr. 1, 2003; accepted Apr. 2, 2003.

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