Activation of the endocannabinoid system by organophosphorus nerve agents
Activation of the endocannabinoid system by organophosphorus nerve agents
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DOI：
10.1038/nchembio.86
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发表时间：
2008-06-01
影响因子：
14.8
通讯作者：
Casida, John E.
中科院分区：
文献类型：
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作者：
Nomura, Daniel K.;Blankman, Jacqueline L.;Casida, John E.
三角洲(9)-四氢大麻酚(THC)是大麻的精神活性成分，具有有用的药用特性，但也有不良副作用。大脑中THC的受体CB1也被内源性大麻素和2-花生四烯基甘油(2-AG)激活。与CB1激动剂相比，通过阻断其代谢来增强内源性大麻素信号可能提供了一种更具选择性的药理学方法。与这一前提相一致的是，脂肪酸酰胺水解酶(FAAH)的抑制剂在没有认知缺陷的情况下产生了镇痛和缓解焦虑的效果。相反，我们发现，被选定的有机磷制剂双重阻断内源性大麻素降解酶单酰甘油脂肪酶(MAGL)和FAAH会导致大脑中2-AG和ANANDAME水平增加十倍以上，并产生强烈的CB1依赖行为效应，反映了CB1激动剂所观察到的效果。有机磷制剂降低花生四烯酸水平的幅度相当于2-AG的升高，这表明内源性大麻素和二十烷酸信号通路在脑内可能是协同调节的。
Delta(9)-Tetrahydrocannabinol (THC), the psychoactive ingredient of marijuana, has useful medicinal properties but also undesirable side effects. The brain receptor for THC, CB1, is also activated by the endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG). Augmentation of endocannabinoid signaling by blockade of their metabolism may offer a more selective pharmacological approach compared with CB1 agonists. Consistent with this premise, inhibitors of the anandamide-degrading enzyme fatty acid amide hydrolase (FAAH) produce analgesic and anxiolytic effects without cognitive defects. In contrast, we show that dual blockade of the endocannabinoid-degrading enzymes monoacylglycerol lipase (MAGL) and FAAH by selected organophosphorus agents leads to greater than ten-fold elevations in brain levels of both 2-AG and anandamide and to robust CB1-dependent behavioral effects that mirror those observed with CB1 agonists. Arachidonic acid levels are decreased by the organophosphorus agents in amounts equivalent to elevations in 2-AG, which indicates that endocannabinoid and eicosanoid signaling pathways may be coordinately regulated in the brain.