RT Journal Article SR Electronic T1 Deletion of CCK2 Receptor in Mice Results in an Upregulation of the Endogenous Opioid System JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 2005 OP 2011 DO 10.1523/JNEUROSCI.22-05-02005.2002 VO 22 IS 5 A1 Blandine Pommier A1 Françoise Beslot A1 Axelle Simon A1 Matthieu Pophillat A1 Toshimitsu Matsui A1 Valérie Dauge A1 Bernard P. Roques A1 Florence Noble YR 2002 UL http://www.jneurosci.org/content/22/5/2005.abstract AB 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, δ, 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 CCK2receptors in opioid-dependent responses.