The effects of
cholecystokinin octapeptide sulphated (CCK) and the potent CCK antagonist
MK-329 (L-364, 718) on
analgesia induced by
morphine in the paw pressure test in the rat were examined. Both CCK (4-16 micrograms/kg) and
MK-329 (0.1-8.0 mg/kg) had no significant effect on thresholds for
pain when given alone, whereas
morphine (2-16 mg/kg) induced dose-dependent
analgesia.
Cholecystokinin (4-16 micrograms/kg) abolished the
analgesia induced by 8 mg/kg
morphine. In contrast, doses of 1 and 2 mg/kg
MK-329 enhanced the
analgesia induced by 8 and 4 mg/kg
morphine, respectively. The present data are consistent with previous reports that CCK blocks, and CCK antagonists enhance,
opiate-induced
analgesia in response to thermal
pain stimuli. In addition, the results show that CCK/
opiate interactions extend to mechanical
pain stimuli. Recent
ligand binding studies have shown that
CCK receptors in the spinal cord of the rat (where CCK/
opiate interactions are thought to occur) are predominantly of the CCK-B subtype. The
drug MK-329 has a relatively weak (micromolar) affinity for
CCK-B receptors and a high affinity (nanomolar) for CCK-A receptors. As relatively large doses (1-2 mg/kg) of
MK-329 are required to enhance
opiate-induced
analgesia in the paw pressure test and tail flick test in rats it appears that CCK/
opiate interactions in this species involve
CCK-B receptors.