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.
Itoh
A
A
Department of Neuropsychopharmacology and Hospital Pharmacy, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, 466-8560, Nagoya, Japan.
Shiotani
T
T
Nakayama
S
S
Mamiya
T
T
Hasegawa
T
T
Noda
Y
Y
Nabeshima
T
T
D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism / Q000502:physiology*; D004361:Drug Tolerance; D008297:Male; D051379:Mice; D009020:Morphine / Q000494:pharmacology; D009021:Morphine Dependence / Q000517:prevention & control*; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D009294:Narcotics / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D011760:Pyrrolidinones / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D013806:Theophylline / Q000494:pharmacology; D014970:Xanthines / Q000494:pharmacology
D009292:Narcotic Antagonists; D009294:Narcotics; D010726:Phosphodiesterase Inhibitors; D011619:Psychotropic Drugs; D011760:Pyrrolidinones; D014970:Xanthines; C058876:nefiracetam; D009270:Naloxone; D009020:Morphine; D013806:Theophylline; C034347:enprofylline; D000242:Cyclic AMP