EFFECTS OF CERULEIN AND CCK ANTAGONISTS ON TOLERANCE INDUCED TO MORPHINE ANTINOCICEPTION IN MICE

Different groups of mice received one daily dose (50 mg/kg) of morphin e subcutaneously (SC) for 3, 4 or 5 days to develop tolerance to the o pioid. The antinociceptive response of morphine (9 mg/kg) was tested i n the hot-plate test 24 h after the last dose of the drug. Tolerance t o morphine was obtained in all groups. The group of mice that received morphine for 4 days was employed for the rest of the experiments. Pre treatment of animals with a single dose of caerulein (0.025, 0.05, and 0.1 mg/kg, SC) 30 min prior to receiving morphine (50 mg/kg; during t he development of tolerance to the opioid) on day 1, 2, 3, 4 or 5 of m orphine administration potentiate antinociception induced by morphine (test dose of 9 mg/kg). The dose of 0.05 mg/kg of caerulein, used 30 m in before morphine administration on day 3, was also used to evaluate the effects of antagonists on caerulein-induced decrease in tolerance. The selective cholecystokinin (CCK) receptor antagonists, MK-329 [1-m ethyl-3-(2 ndoloyl)amino-5-phenyl-3H-1,4-benzodiazepin-2-one; 0.25 and 0.5 mg/kg] or L-365,260 H-1,4-benzodiazepin-3-yl]-N-(3-methyl-phenyl) urea; 0.25 and 0.5 mg/kg] decreased potentiation of morphine response induced by caerulein. MK-329 or L365,260, when were injected 35 min be fore morphine injection during the development of tolerance and on day 3, decreased the tolerance to morphine. A single administration of MK -329 or L-365,260 (in the absence of caerulein) 35 min and 48 h before the test dose of morphine (9 mg/kg) potentiated the antinociception o f morphine in nontolerant animals. In conclusion, CCK mechanism(s) may interact with morphine tolerance. (C) 1997 Elsevier Science Inc.