On the mechanism(s) of cholecystokinin (CCK): receptor stimulation attenuates morphine dependence in mice

In the present study, effect of cholecystokinin (CCK) agonists and on dependence to morphine in mice has been investigated. The influence of dopaminergic, adrenergic, cholinergic and serotonergic on attenuation of naloxone-induced jumping in morphine-dependent mice by CCK agonists were also considered. Mice were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily (10 a.m. 1 p.m. and 4 p.m.) for 3 days, and a last dose of morphine (50 mg/kg) was administered on the 4th day. Withdrawal syndrome (jumping) was precipitated by naloxone (5 mg/kg) which was administered intraperitoneally 2 hr after the last dose of morphine. To study effects of CCK receptor agonists, 10 injection of morphine (3 administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. The CCK agonists CCK-8 (0.001-0.1 mg/kg), unsulfated CCK-8 (CCK-8U; 0.001-0.1 mg/kg) and caerulein (0.00001-0.01 mg/kg) were able to prevent withdrawal signs precipitated by naloxone (5 mg/kg). Sulpiride and pimozide increased response induced by CCK-8 agonists. The dopamine antagonists also attenuates jumping by themselves. SCH 23390 did not alter the CCK-8 effect, but decreased the jumping by itself. Phenoxybenzamine, propranolol, methysergide and atropine did not change the caerulein effect significantly. However, single administration of atropine increased and methysergide decreased jumping. It is concluded that CCK mechanism(s) may be involved in morphine dependence, and dopaminergic mechanism(s) may interact with CCK in attenuation of naloxone-induced jumping.