1 Although cholecystokinin octapeptide sulphate (CCK-8) activates the opioid system of isolated guinea-pig ileum (GPI) whether it activates the m-or k-system, or both, remains unclear. Neither is it known whether CCK-8 in¯uences the withdrawal responses in GPI preparations brie¯y exposed to opioid agonists. This study was designed to clarify whether CCK-8 activates m-or k-opioid systems or both; and to investigate its eect on the withdrawal contractures in GPI exposed to m-or kagonists and on the development of tolerance to the withdrawal response. 2 In GPI exposed to CCK-8, the selective k-antagonist nor-binaltorphimine elicited contractile responses that were concentration-related to CCK-8 whereas the selective m-antagonist cyprodime did not. 3 In GPI preparations brie¯y exposed to the selective m-agonist, dermorphin, or the selective kagonist, U-50, 488H, and then challenged with naloxone, CCK-8 strongly enhanced the withdrawal contractures. 4 During repeated opioid agonist/CCK-8/opioid antagonist tests tolerance to opioid-induced withdrawal responses did not develop. 5 These results show that CCK-8 preferentially activates the GPI k-opioid system and antagonizes the mechanism(s) that control the expression of acute dependence in the GPI.