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抑制脊髓转化生长因子β激活激酶影响大鼠鞘内吗啡耐受的信号机制研究
Identification of the signaling pathway involved in 5Z-7-oxozeaenol attenuating intrathecal morphine tolerance in rats
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DOI:
作者:
徐昊,许涛,马霞青,江伟
Xu Hao, Xu Tao, Ma Xia Qing, Jiang Wei
作者单位:
上海市第六人民医院麻醉科
Department of Anesthesiology, the sixth hospital of Shanghai
关键词:
吗啡耐受;转化生长因子β激活激酶; c-Jun氨基末端激酶(JNK);p38丝裂原活化蛋白激酶
morphine tolerance; Transforming growth factor-activated kinase 1,TAK1; p38 mitogen-activated protein kinases,p38 MAPK; c-Jun N-terminal kinase, JNK
摘要:
目的 探讨转化生长因子β激活激酶(Transforming growth factor-activated kinase 1,TAK1)选择性抑制剂5Z-7-oxozeaenol缓解慢性吗啡耐受的信号机制。方法 健康雄性SD大鼠,体重220~250g,按Yaksh法行鞘内置管。取40只置管成功的大鼠随机分成5组(n=8):对照组(C组)鞘内给予10μl生理盐水;吗啡组(M组)鞘内给予15μg吗啡/10μl生理盐水;抑制剂+生理盐水组(IS组)鞘内给予1μg 5Z-7-oxozeaenol /10μl 20%DMSO,30分钟后给予15μg吗啡/10μl生理盐水;20%DMSO+吗啡合用组(DM组)鞘内给予10μl 20%DMSO,30分钟后给予15μg吗啡/10μl生理盐水;抑制剂+吗啡合用组(IM组)鞘内给予1μg 5Z-7-oxozeaenol/10μl 20%DMSO,30分钟后给予15μg吗啡/10μl生理盐水。每天给药一次,连续给药7天。每天给药结束30分钟后行缩爪实验测大鼠缩爪痛阈值,并计算最大抗伤害效应百分比(MPEP)。给药最后一天,大鼠断头取脊髓腰膨大。免疫印迹法测脊髓内JNK及p38 MAPK表达及磷酸化水平。结果5Z-7-oxozeaenol与吗啡合用可有效缓解吗啡耐受并下调TAK1蛋白表达,且显著降低慢性吗啡处理所致脊髓内JNK及p38 MAPK磷酸化水平的增高。结论 5Z-7-oxozeaenol通过下调TAK1/JNK及TAK1/p38 MAPK活化水平缓解吗啡耐受。
Objective To explore the signaling pathway involved in 5Z-7-oxozeaenol, a selective inhibitor of transforming growth factor-activated kinase 1, alleviating the development of tolerance to morphine antinociception in rats. Method Forty Male SD rats weighting 220~250g in which polyethylene catheter were inserted according toYaksh were randomly divided into 5 groups (n = 8): control group (group C, 10μl saline i.t.), 5Z-7-oxozeaenol plus saline group (group IS, 1μg 5Z-7-oxozeaenol in 10 μl 20% DMSO followed by 10 μl saline i.t.), chronic morphine group (group M, 15μg morphine in 10 μl saline i.t.), 20%DMSO plus morphine group (group DM, 10 μl 20%DMSO followed by 15μg morphine in 10 μl saline i.t.), 5Z-7-oxozeaenol plus morphine group (group IM, 1μg 5Z-7-oxozeaenol in 10 μl 20% DMSO followed by 15 μg morphine in 10 μl saline i.t.). An interval of 30 minutes was required between two drug challenges on each day. Drugs administrated daily for 7 consecutive days. Paw withdraw threshold was measured 30 minutes after daily injection. Percentage of maximum possible effect (MPEP) was calculated. Animals were sacrificed on the last day, and lumbar spinal cords were harvested. Western blot analysis was used to detect JNK and p38 MAPK protein expressions, as well as phosphorylation of JNK and p38 MAPK. Results 5Z-7-oxozeaenol co-administrated with morphine attenuated the development of morphine tolerance, and suppressed the up-regulation of TAK1 protein levels, as well as JNK and p38 MAPK phosphorylation induced by chronic morphine treatment. Conclusions 5Z-7-oxozeaenol may alleviate morphine tolerance through down-regulating TAL1/JNK and TAK1/p38 MAPK activation.
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