Modulation of the in vivo actions of morphine by the mixed CCKA/B receptor antagonist PD 142898.

Abstract The ability of a mixed CCK A B receptor antagonist PD 142898 (benzenebutanic acid, β-[[3-(1 H -indol-3-yl)-2-methyl-2-[[[(2-methyl-cyclohexyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-[1 S -[1α[ S∗ ( R∗ )]-2β]]) to modulate the antinociceptive, positive reinforcing and gastrointestinal actions of morphine was investigated in the rat. PD 142898 antagonised the development and maintenance of morphine (2.0 mg/kg, s.c.) induced conditioned place preference at 0.1 mg/kg, i.p. However, it potentiated the antinociceptive action of a subthreshold dose of morphine in the radiant tail flick model at doses of 0.001 and 0.01 mg/kg, s.c. Furthermore, PD 142898 (0.0001–1.0 mg/kg, s.c.) also potentiated the antinociceptive action of morphine (1.0 mg/kg, s.c.) against the late phase of formalin response associated with inflammation at the dose of 0.001 mg/kg. PD 142898 (0.001 mg/kg, s.c.) blocked the development of tolerance to morphine in the formalin test. It failed (0.001–1.0 mg/kg, i.p.) to modulate the inhibitory action of morphine (5.0 mg/kg, s.c.) on gastrointestinal transit as measured using the charcoal meal test. It is argued that the effect of PD 142898 in the conditioned place preference test involves antagonism of CCK A receptors, whilst the potentiation of the antinociceptive action of morphine is mediated via blockade of CCK B receptors. These results suggest that the mixed CCK A/B receptor antagonist may potentiate the analgesic action of morphine, block the development of tolerance without a concomitant increase in constipation and may also reduce the abuse potential of the opiate.