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The Journal of Neuroscience, September 15, 1998, 18(18):7285-7295

Activity of the -Opioid Receptor Is Partially Reduced, Whereas Activity of the -Receptor Is Maintained in Mice Lacking the µ-Receptor

H. W. D. Matthes¹, C. Smadja², O. Valverde², J.-L. Vonesch³, A. S. Foutz⁴, E. Boudinot⁴, M. Denavit-Saubié⁴, C. Severini⁵, L. Negri⁵, B. P. Roques², R. Maldonado², and B. L. Kieffer¹

¹ Unité Propre de Recherche 9050 Centre National de la Recherche Scientifique, Ecole Supérieure de Biotechnologie de Strasbourg Université Louis Pasteur, F-67400 Illkirch, Strasbourg, France, ² Département de Phamacochimie Moléculaire et Structurale, Institut National de la Santé et de la Recherche Médicale U266, Unité de Recherche Associée D1500 Centre National de la Recherche Scientifique, Université René Descartes, F-75270 Paris, France, ³ Institut de Génétique et Biologie Moléculaire et Cellulaire, F-67404 Illkirch Strasbourg, France, ⁴ Biologie Fonctionnelle du Neurone, Institut A. Fessard, Centre National de la Recherche Scientifique, F-91198 Gif-sur-Yvette, France, and ⁵ Institute of Medical Pharmacology, University of Rome "La Sapienza", 00185 Rome, Italy

Previous pharmacological studies have indicated the possible existence of functional interactions between µ-, - and -opioid receptors in the CNS. We have investigated this issue using a genetic approach. Here we describe in vitro and in vivo functional activity of - and -opioid receptors in mice lacking the µ-opioid receptor (MOR). Measurements of agonist-induced [³⁵S]GTPS binding and adenylyl cyclase inhibition showed that functional coupling of - and -receptors to G-proteins is preserved in the brain of mutant mice. In the mouse vas deferens bioassay, deltorphin II and cyclic[D-penicillamine², D-penicillamine⁵] enkephalin exhibited similar potency to inhibit smooth muscle contraction in both wild-type and MOR / mice. -Analgesia induced by deltorphin II was slightly diminished in mutant mice, when the tail flick test was used. Deltorphin II strongly reduced the respiratory frequency in wild-type mice but not in MOR / mice. Analgesic and respiratory responses produced by the selective -agonist U-50,488H were unchanged in MOR-deficient mice. In conclusion, the preservation of - and -receptor signaling properties in mice lacking µ-receptors provides no evidence for opioid receptor cross-talk at the cellular level. Intact antinociceptive and respiratory responses to the -agonist further suggest that the -receptor mainly acts independently from the µ-receptor in vivo. Reduced -analgesia and the absence of -respiratory depression in MOR-deficient mice together indicate that functional interactions may take place between µ-receptors and central -receptors in specific neuronal pathways.

Key words: µ-opioid receptor knock-out; µ---opioid receptor interactions; G-protein coupling; - analgesia; respiration; vas deferens

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18187285-11$05.00/0

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