Cholecystokinin B antagonists strongly potentiate antinociception mediated by endogenous enkephalins

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.