MODULATION OF THE IN-VIVO ACTIONS OF MORPHINE BY THE MIXED CCKA B-RECEPTOR ANTAGONIST PD-142898/

The ability of a mixed CCKA/B receptor antagonist PD 142898 (benzenebu tanic acid, exyl)oxy]carbonyl]amino]-1-oxopropyl]amino]-[1S-[1 alpha[S (R*)]-2 beta]]) 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 inflammati on at the dose of 0.001 mg/kg. PD 142898 (0.001 mg/kg, s.c.) blocked t he development of tolerance to morphine in the formalin test. It faile d (0.001-1.0 mg/kg, i.p.) to modulate the inhibitory action of morphin e (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 c onditioned place preference test involves antagonism of CCKA receptors , whilst the potentiation of the antinociceptive action of morphine is mediated via blockade of CCKB receptors. These results suggest that t he mixed CCKA/B receptor antagonist may potentiate the analgesic actio n of morphine, block the development of tolerance without a concomitan t increase in constipation and may also reduce the abuse potential of the opiate.