CCK receptor activation may prevent tolerance to morphine in mice

Abstract

Different groups of mice were treated with morphine (50 mg/kg s.c.) once daily for 1, 2, 3, 4, or 5 days, in order to develop tolerance to the drug. The antinociceptive effect of morphine (9 mg/kg s.c.) was tested 24 h after each dose of the drug administration. Tolerance to morphine reached its peak on the 4th day. Daily pretreatment of animals for a period of 4 days with different doses of cholecystokinin octapeptide (CCK-8; 0.001, 0.01, 0.05 and 0.1 mg/kg s.c.), caerulein (0.0001, 0.001, 0.005 and 0.01 mg/kg s.c.) but not unsulfated cholecystokinin octapeptide (0.001, 0.01 or 0.1 mg/kg s.c.) 30 min before daily administration of morphine (50 mg/kg s.c.) prevented the development of tolerance. A group of animals received a single dose of caerulein (0.005 mg/kg), CCK-8 (0.01 mg/kg) or unsulfated CCK-8 (0.01 mg/kg) 30 min before morphine injection (50 mg/kg s.c.) on the 3rd or 4th day. In these animals, which were tested for antinociception on the 5th day, tolerance to the drug (3, 6 and 9 mg/kg s.c.) was also decreased by caerulein, CCK-8 but not unsulfated CCK-8. In a group of mice in which peptides were administered 30 min prior to the doses of morphine (3, 6 or 9 mg/kg s.c.) on the 5th day, similar results were obtained. The results of the present study indicate that activation of both CCK B and CCK A receptors may prevent the development of tolerance to morphine, and the sulfate group in the CCK-8 molecule may be essential for the tolerance inhibition.