title: Deletion of CCK2 receptor in mice results in an upregulation of the endogenous opioid system.
abstract: 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 mu, delta, 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.
authors.affiliation: 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, Paris Cedex 06, France.
authors.forename: Blandine
authors.initials: B
authors.lastname: Pommier
authors.forename: Françoise
authors.initials: F
authors.lastname: Beslot
authors.forename: Axelle
authors.initials: A
authors.lastname: Simon
authors.forename: Matthieu
authors.initials: M
authors.lastname: Pophillat
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Matsui
authors.forename: Valérie
authors.initials: V
authors.lastname: Dauge
authors.forename: Bernard P
authors.initials: BP
authors.lastname: Roques
authors.forename: Florence
authors.initials: F
authors.lastname: Noble
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000701:Analgesics, Opioid / Q000378:metabolism; D000818:Animals; D001667:Binding, Competitive; D001923:Brain Chemistry; D004789:Enzyme Activation / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005260:Female; D006930:Hyperalgesia / Q000235:genetics / Q000503:physiopathology / Q000517:prevention & control; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000235:genetics; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D018847:Opioid Peptides / Q000378:metabolism* / Q000494:pharmacology; D010147:Pain Measurement / Q000187:drug effects; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin / Q000172:deficiency* / Q000235:genetics; D011957:Receptors, Opioid / Q000819:agonists; D013375:Substance Withdrawal Syndrome / Q000235:genetics; D015854:Up-Regulation / Q000502:physiology*
chemical_list: D000701:Analgesics, Opioid; D004791:Enzyme Inhibitors; D018691:Excitatory Amino Acid Antagonists; D008565:Membrane Proteins; D009292:Narcotic Antagonists; D009294:Narcotics; D018847:Opioid Peptides; D043887:Receptor, Cholecystokinin B; D011949:Receptors, Cholecystokinin; D011957:Receptors, Opioid; D009020:Morphine; D000262:Adenylyl Cyclases