The effects of intrathecal (i.t.) co-administration of the cholecystokinin (CCK) antagonists lorglumide or proglumide with a "low" (1 microgram) and "high" (10 micrograms) dose of i.t. morphine on the development of opioid tolerance were determined using the rat tail-flick assay. Although co-injection of 7 ng lorglumide or 20 ng proglumide (doses which have been demonstrated to acutely enhance 1 microgram morphine, i.t.) were without effect, co-administration of 70 ng lorglumide or 64 ng proglumide with 1 microgram morphine for 6 days inhibited development of tolerance to this dose of opioid. Higher doses of CCK antagonists (1400 ng lorglumide and 1280 ng proglumide) were required to prevent the tolerance induced by 10 micrograms morphine. These findings provide further evidence that CCK mediates, at least partially, tolerance which develops to the analgesic effect of opioids and indicate the involvement of CCK pathways in the spinal cord. The results are also consistent with a mechanism in which the level of activation of compensatory, anti-opioid CCK circuitry is increased in proportion to the functional level of opioid pathways.