The enhancement of morphine antinociception by a CCKB receptor antagonist in the rat depends on the phase of inflammation and the intensity of carrageenin-induced hyperalgesia.

The ability of the cholecystokinin B (CCKB) receptor antagonist L-365,260 to modulate the antinociceptive action of systemic morphine was investigated using the well established rat model of localized inflammation induced by intraplantar injection of carrageenin. The effects of morphine (0.1-1 mg/kg i.v.) alone or in combination with the CCKB receptor antagonist (0.2 mg/kg s.c.) were determined at different time-points (at 1, 3 and 24 h) after the injection of carrageenin by measuring the vocalization threshold to paw pressure. L-365,260 was found to be ineffective in modulating the responses to all doses of morphine at 1 and 24 h after carrageenin. By contrast, at 3 h, the CCKB receptor antagonist reversed the ineffectiveness of the low dose (0.1 mg/kg i.v.) of morphine on the inflamed paw. Further, in the L-365,260-pretreated rats, a significant correlation between the antinociceptive effect of the low dose (0.1 mg/kg) of morphine and the intensity of the mechanical hyperalgesia was observed, indicating that the CCK control of the degree of sensitivity to opioids can vary among-the animals. Our data illustrate a differential and limited effect of L-365,260 on opioid antinociception in carrageenin-injected rats, depending on the dose of morphine, the phase of inflammation and the intensity of hyperalgesia.