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Inhibition of the development of morphine tolerance

抑制吗啡耐受的发展

基本信息

批准号：
04671223
负责人：
MATSUMOTO Ken
金额：
$ 1.34万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1992
资助国家：
日本
起止时间：
1992 至 1993
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-04671223/
关键词：
Morphine Tolerance Cross-tolerance Calcium Calcium channel クロニジン

项目摘要

1. In acetic acid-induced writhing test, intraperitoneal administration of clonidine exhibited the analgesic effect in a does dependent manner. The decrease in morphine-induced analgesia was also observed following prolonged administration of clonidine. Furthermore, intracerebroventricular administrations of omega-conotoxin, a selective N-type calcium channel antagonist, have exhibited the analgesic effect and these action were mimicked in morphine chronic administered mice.2. Significant decrease in ^3H-PN-200-110 binding to cortical membrane fraction was observed in clonidine-tolerant mice whereas increase in morphine-tolerant mice. In contrast, significant increase of ^<125>I-omega-conotoxin bindings were observed in clonidine- or morphine-tolerant group. These results suggested that cross-tolerance may develop between clonidine and morphine through the change in L or N-type calcium channels.3. In the measurement of intracellular concentration of Ca^<2+> ([Ca_<2+>]i) in human neuroblastoma SH-SY5Y cells, morphine or clonidine inhibited carbachol-induced calcium influx dose-dependent manner and these actions were inhibited by naloxone or yohimbine, respectively.4. In photoaffinity labelling and SDS-PAGE experiments, specific accumulation (220-300 KDa) of ^<125>I-omega-conotoxin were observed in mice cortical membrane fractions. Significant increase of these accumulation were also observed in membrane fractions obtained from mice following chronic administration with morphine or clonidine.Above results suggest N-type calcium channels may have a possible role in the formation of morphine tolerance and cross-tolerance between morphine and clonidine.

1.在乙酸引起的扭体试验中，腹腔注射可乐定表现出剂量依赖的镇痛效果。长期服用可乐定后也观察到吗啡引起的镇痛作用下降。此外，脑室内注射omega-芋螺毒素（一种选择性N型钙通道拮抗剂）也表现出镇痛作用，并且在吗啡长期给药的小鼠中模拟了这些作用。 2．在可乐定耐受小鼠中观察到^3H-PN-200-110与皮质膜部分的结合显着减少，而在吗啡耐受小鼠中观察到增加。相反，在可乐定或吗啡耐受组中观察到125 I-omega-芋螺毒素结合显着增加。这些结果提示，可乐定与吗啡之间可能通过L型或N型钙通道的改变而产生交叉耐受。 3．在人神经母细胞瘤SH-SY5Y细胞胞内Ca^2+([Ca_2+]i)浓度测定中，吗啡或可乐定以剂量依赖性方式抑制卡巴胆碱诱导的钙内流，纳洛酮或育亨宾分别抑制这种作用。 4．在光亲和标记和SDS-PAGE实验中，在小鼠皮质膜级分中观察到125 I-omega-芋螺毒素的特异性积累(220-300KDa)。在长期服用吗啡或可乐定后，从小鼠获得的膜组分中也观察到这些积累的显着增加。上述结果表明，N-型钙通道可能在吗啡耐受性以及吗啡和可乐定之间的交叉耐受性的形成中发挥作用。