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The Journal of Neuroscience, March 1, 2002, 22(5):2005-2011

Deletion of CCK₂ Receptor in Mice Results in an Upregulation of the Endogenous Opioid System

Blandine Pommier¹, Françoise Beslot¹, Axelle Simon¹, Matthieu Pophillat¹, Toshimitsu Matsui², Valérie Dauge¹, Bernard P. Roques¹, and Florence Noble¹

¹ Département de Pharmacochimie Moléculaire et Structurale, Institut National de la Santé et de la Recherche Médicale U266-Centre National de la Recherche Scientifique Unité Mixte de Recherche 8600, Unité de Formation et de Recherche des Sciences Pharmaceutiques et Biologiques, 75270 Paris Cedex 06, France, and ² Third Division Department of Medecine, Kobe University School of Medecine, Chuo-ku Kobe 650-0017, Japan

Stimulation of the brain CCK₂ receptor by the C-terminal octapeptide CCK₈ of cholecystokinin (CCK) negatively modulates opioid responses. This suggests the existence of physiologically relevant interactions between endogenous CCK and opioid peptides, opening new perspectives particularly in the treatment of pain or drug addiction. CCK₂ receptor-deficient mice were used to analyze the incidence of this gene invalidation on opioid system. Compared with wild-type mice, mutants exhibited the following: (1) a hypersensitivity to the locomotor activity induced by inhibitors of enkephalin catabolism or by morphine; (2) a spontaneous hyperalgesia to thermal nociceptive stimulus, which was reversed by previous administration of the NMDA antagonist MK-801 [(+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d] cyclohepten-5,10-imine maleate], and a large reduction in analgesic effects of endogenous or exogenous opioids; and (3) a more severe withdrawal syndrome after chronic morphine treatment. As expected, stimulation of µ, , and D₂ receptors on brain tissue of wild-type animals induced a dose-dependent decrease in adenylate cyclase activity, whereas a striking mirror effect was observed in mutants. All of these results suggest that the absence, in knock-out mice, of the negative feedback control on the opioid system, normally performed out by CCK₂ receptor stimulation, results in an upregulation of this system. These biochemical and pharmacological results demonstrate the critical role played by CCK₂ receptors in opioid-dependent responses.

Key words: cholecystokinin; opioid; mutant mice; adenylyl cyclase; binding; behavior

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Copyright © 2002 Society for Neuroscience  0270-6474/02/2252005-07$05.00/0

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