Attenuation of the development of morphine dependence/tolerance by nefiracetam: involvement of adenosine 3′:5′-cyclic monophosphate system

Biochemical changes such as intracellular cAMP and Ca 2+ underlying morphine dependence and tolerance have been suggested. Therefore, we investigated the effects of nefiracetam ( N-(2,6-dimethyl-phenyl)-2(2-oxo-1-pyrrolidinyl) acetamide), which increases intracellular cAMP and Ca 2+ levels, on the development of morphine dependence and tolerance. Mice administered morphine (6 or 20 mg kg −1) twice daily for 5 days, showed withdrawal symptoms (jumping, diarrhea and body weight loss) after naloxone challenge (5 mg kg −1), indicating morphine dependence. Furthermore, tolerance to the analgesic effect of morphine was observed in these mice. Co-administration of nefiracetam (5 or 10 mg kg −1) with morphine during the pretreatment period, significantly reduced the signs of withdrawal symptoms, moreover, the tolerance was significantly attenuated. Elevation of cAMP levels in the cortex was observed in morphine-dependent mice, but not in mice co-administered nefiracetam. Acute administration of nefiracetam shows no effect on the withdrawal symptoms and the analgesic effect in morphine-naive mice. Theophylline (3 or 10 mg kg −1) tended to attenuate and enprofylline (10 or 30 mg kg −1) significantly attenuated the development of morphine dependence and tolerance. These findings suggest that co-administration of nefiracetam or compounds, which increase the cAMP level, may be a useful strategy for attenuating the development of morphine dependence and tolerance in the clinic.