Cholecystokinin B antagonists strongly potentiate antinociception mediated by endogenous enkephalins

O Valverde, R Maldonado, MC Fournie-Zaluski and BP Roques

Departement de Pharmacochimie Moleculaire et Structurale, I.N.S.E.R.M.- U.R.A., U.F.R. des Sciences Pharmaceutiques et Biologiques, Faculte de Pharmacie, Universite Rene Descartes, Paris, France.

The effects of pretreatment with the selective cholecystokinin (CCK) B antagonists (3R-(+)-N-(2,3-dihydro-1-methyl-2-oxo-5-phenyl-1H-1, 4- benzodiazepin-3-yl)-N1-(3-methylphenyl urea (L-365,260), 4-([2-[[3-(1H- indol-3-yl)-2-methyl-1-oxo-2-[[tricyclo[3.3, 1.1(3.7)]dec-2- yloxy)carbonyl]amino]propyl]amino]-1-phenylethyl] amin)-4-oxo-[R- (R*,R*)]butanoate-N-methyl-D-glucamine (PD-134,308) and N-(2- adamantyloxycarbonyl)-D-alpha-methyltryptophanyl-[N-(2- (4- chlorophenyl)ethyl)]glycine (RB 211), on the naloxone-reversible, antinociceptive responses induced by systemic (i.v.) administration of the complete inhibitor of the enkephalin-catabolizing enzymes, N- ((R,S,)-2-benzyl-3[(S)-(2-amino-4-methylthio)butyldithio]-1- oxopropyl)- L-phenylalanine benzyl ester (RB 101), were determined in rat tail- flick and mouse hot-plate tests. L-365,260 (0.12, 0.25 and 0.5 mg/kg s.c.), PD-134,308 (0.3, 1 and 3 mg/kg i.p.) and RB 211 (0.5, 1 and 1.5 mg/kg i.p.) strongly potentiated the antinociceptive effects induced by RB 101 in the rat tail-flick test, in which spinal control of nociception is predominant. Thus, the antinociception observed after the association of L-365,260 (0.5 mg/kg), RB 211 (1.5 mg/kg) or PD- 134,308 (3 mg/kg) with RB 101 (5 mg/kg) was, respectively, 300, 500 and 800% higher than that observed with RB 101 given alone. This facilitatory effect was partially blocked by the administration of naloxone (1 mg/kg s.c.). Under the same conditions the potentiation of the antinociceptive response produced by morphine (0.1-4 mg/kg s.c.) was inferior to 250%. In the mouse hot-plate test, L-365,260 (0.02 and 0.1 mg/kg i.p.) and PD-134,308 (0.3, 1 and 3 mg/kg i.p.) also enhanced endogenous enkephalin induced antiociception, but this potentiating effect, completely reversed by administration of naloxone (0.1 mg/kg s.c.), was about 2 times less effective than in the tail-flick assay. The present findings demonstrate an opposing physiological role of endogenous CCK, acting on CCK B receptors, and opioid peptides in the control of pain perception at both spinal and supraspinal levels. These results could have important clinical applications because a combination of a CCK B antagonist and RB 101, which has been showed to be almost devoid of morphine side effects, would increase the overall antinociceptive efficacy into a range that will be more clinically useful.

Volume 270, Issue 1, pp. 77-88, 07/01/1994
Copyright © 1994 by American Society for Pharmacology and Experimental Therapeutics

This article has been cited by other articles:

				F. Benedetti, M. Amanzio, S. Vighetti, and G. Asteggiano The Biochemical and Neuroendocrine Bases of the Hyperalgesic Nocebo Effect. J. Neurosci., November 15, 2006; 26(46): 12014 - 12022. [Abstract] [Full Text] [PDF]

				B. Pommier, F. Beslot, A. Simon, M. Pophillat, T. Matsui, V. Dauge, B. P. Roques, and F. Noble Deletion of CCK2 Receptor in Mice Results in an Upregulation of the Endogenous Opioid System J. Neurosci., March 1, 2002; 22(5): 2005 - 2011. [Abstract] [Full Text] [PDF]

				M. M. Heinricher, S. McGaraughty, and V. Tortorici Circuitry Underlying Antiopioid Actions of Cholecystokinin Within the Rostral Ventromedial Medulla J Neurophysiol, January 1, 2001; 85(1): 280 - 286. [Abstract] [Full Text] [PDF]

				A. E. Friedrich and G. F. Gebhart Effects of Spinal Cholecystokinin Receptor Antagonists on Morphine Antinociception in a Model of Visceral Pain in the Rat J. Pharmacol. Exp. Ther., February 1, 2000; 292(2): 538 - 544. [Abstract] [Full Text]

				F. Noble, S. A. Wank, J. N. Crawley, J. Bradwejn, K. B. Seroogy, M. Hamon, and B. P. Roques International Union of Pharmacology. XXI. Structure, Distribution, and Functions of Cholecystokinin Receptors Pharmacol. Rev., December 1, 1999; 51(4): 745 - 781. [Abstract] [Full Text] [PDF]

				P. Honoré, J. Buritova, M.-C. Fournié-Zaluski, B. P. Roques, and J.-M. Besson Antinociceptive Effects of RB101, a Complete Inhibitor of Enkephalin-catabolizing Enzymes, Are Enhanced by a Cholecystokinin Type B Receptor Antagonist, as Revealed by Noxiously Evoked Spinal c-Fos Expression in Rats J. Pharmacol. Exp. Ther., April 1, 1997; 281(1): 208 - 217. [Abstract] [Full Text]