Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718.

The potent and selective non-peptide cholecystokinin (CCK) antagonist L-364,718 (0.5-2.0 mg/kg s.c.) enhanced the analgesia induced by acute morphine treatment in the rat tail flick test. Chronic treatment with L-364,718 (1.0 mg/kg) prevented the development of tolerance to morphine analgesia (after a 6 day period of morphine treatment) but did not influence the onset of opioid dependence. Since L-364,718 is considerably more potent in inhibiting CCK binding to peripheral tissues than to brain membranes its interaction with morphine is surprising. The exact locus of this interaction, or whether it involves 'peripheral-type' (CCK-A) or 'central-type' (CCK-B) receptors is not known.