A therapeutic strategy to prevent morphine dependence and tolerance by coadministration of cAMP-related reagents with morphine
A therapeutic strategy to prevent morphine dependence and tolerance by coadministration of cAMP-related reagents with morphine
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DOI：
10.1358/mf.1998.20.7.485728
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发表时间：
1998-09-01
影响因子：
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通讯作者：
Nabeshima, T
中科院分区：
文献类型：
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作者：
Itoh, A;Noda, Y;Nabeshima, T
吗啡是目前可用的最有效的阿片类镇痛药，但其用于治疗严重结扎的使用正在增加；长期吗啡暴露指标身体依赖/耐受性。尽管这一现象的机制尚未确定，但一些生化变化，包括细胞内cAMP系统和Ca2+动员，已经提出了评估cAMP的贡献，我们研究了奈非西坦[N-（2,6-二甲基苯基）-2（2-氧-1-吡罗烷基）乙酰胺]和磷酸二酯酶抑制剂（茶碱，enprofylline和罗利普兰）对吗啡依赖/耐受的影响。小鼠给予吗啡（6或10 mg/kg， s.c），每天两次，连续5天。纳洛酮给药（5mg /kg, ig）后出现跳跃、腹泻、体重下降等戒断症状，提示机体对吗啡依赖。此外，在甩尾试验中还观察到吗啡茶对小鼠抗伤害感受性的耐受性。然而;在预处理期间，尼非西坦（5或10 mg/kg， p.o）、恩丙林（30 mg/kg, p.o）和罗利普兰（0.3或1 mg/kg， p.o）与吗啡联合使用可显著减少戒断症状；耐受性明显减弱。急性给药奈非拉西坦不能减轻吗啡对小鼠的戒断症状，也不影响吗啡对小鼠的抗伤害感受作用。茶碱（3或10 mg/kg， p.o.）倾向于减弱吗啡依赖/耐受的发展。目前的研究结果表明，在临床上，增加cAMP水平的化合物与吗啡共同施用可能是一种有效的策略，可以减轻吗啡依赖/耐受的发展。(C) 1998普罗斯科学。版权所有。
Morphine is the most potent opioid analgesic currently available and its use is increasing for treatment of severe pairs however; long-term morphine exposure indices physical dependence/tolerance. Although the mechanisms underlying this phenomenon have not been established, several biochemical changes including intracellular cAMP systems and Ca2+ mobilisation have been suggested To evaluate the contribution of cAMP, we investigated the effects of nefiracetam [N-(2,6-dimethyl-phenyl)-2(2-oxo-1-pyrrolidinyl)acetamide] and phosphodiesterase inhibitors (theophylline, enprofylline and rolipram) on rile development of morphine dependence/tolerance. Mice administered morphine (6 or 10 mg/kg, s.c.) twice daily for 5 days. showed withdrawal signs (jumping, diarrhea and body weight loss) after naloxone challenge (5 mg/kg, i.p.), indicating the physical dependence to morphine. Further the tolerance to antinociceptive effect of morphine teas observed in these mice on the tail-flick test. However; coadministration of nefiracetam (5 or 10 mg/kg, p.o.), enprofylline (30 mg/kg, p.o.) and rolipram (0.3 or 1 mg/kg, ip.) with morphine during the pretreatment period significantly reduced the withdrawal signs, moreover; the tolerance was significantly attenuated. Acute administration of nefiracetam failed to reduce the withdrawal signs qnd did not affect the antinociceptive effect of morphine in morphine-naive mice. Theophylline (3 or 10 mg/kg, p.o.) tended to attenuate the development of morphine dependence/tolerance. The present findings suggest that coadministration of compounds which increase cAMP level with morphine may be a useful strategy to attenuate the development of morphine dependence/tolerance in the clinic. (C) 1998 Prous Science. All rights reserved.