Involvement of cyclic AMP systems in morphine physical dependence in mice:prevention of development of morphine dependence by rolipram, a phosphodiesterase 4 inhibitor

1 In this study, we examined whether morphine dependence was inhibited by r olipram, a cyclic AMP selective phosphodiesterase inhibitor in mice, since a role for the cyclic AMP systems in the development of morphine dependence has been reported. 2 Mice, which received morphine (10 mg kg(-1) s.c.) twice a day for 5 days showed withdrawal syndromes such as jumping, rearing and forepaw tremor fol lowing naloxone challenge (5 mg kg(-1) i.p.) on the 6th day. 3 Such mice exhibited a significant elevation of cyclic AMP levels in the t halamus compared to control mice. However, co-administration of rolipram (1 mg kg(-1) i.p.) with morphine for 5 days significantly attenuated the seve rity of the withdrawal syndrome and the increase in the cyclic AMP levels a fter the administration of naloxone. 4 In naive mice, acute morphine treatment (10 mg kg(-1) s.c.) decreased cyc lic AMP levels in the thalamus and cerebral cortex 10 min later. The decrea se of cyclic AMP levels induced by acute morphine treatment was blocked by co-administration of rolipram (1 mg kg(-1) i.p.). However, acute rolipram d id not affect the naloxone-precipitated morphine withdrawal syndrome. 5 These results suggest that the elevation of the cyclic AMP levels is invo lved in the development of morphine withdrawal syndrome and that blockade o f the morphine-induced reduction of cyclic AMP levels by chronic rolipram i nhibits the development of dependence and the behavioural and biochemical c hanges induced by naloxone. Furthermore, rolipram may be a useful drug for attenuating the development of morphine dependence.