An endocannabinoid mechanism for stress-induced analgesia
An endocannabinoid mechanism for stress-induced analgesia
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DOI：
10.1038/nature03658
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发表时间：
2005-06-23
期刊：
影响因子：
64.8
通讯作者：
Piomelli, D
中科院分区：
文献类型：
--
作者：
Hohmann, AG;Suplita, RL;Piomelli, D
急性应激通过激活参与阿片或非阿片机制的大脑通路来抑制疼痛。在这里，我们表明，这种现象的阿片类药物非依赖形式，称为应激诱导镇痛（1），是由大脑中内源性大麻样（大麻素）化合物的释放介导的。阻断中脑导水管周围灰质中的大麻素CB 1受体可防止非阿片类应激诱导的镇痛在该区域，应激促进两种内源性大麻素的快速形成，脂质2-花生四烯酰甘油（2）（2-AG）和花生四烯酰胺（3）。一种新开发的2-AG失活酶单酰基甘油脂肪酶抑制剂（4，5）选择性增加2-AG浓度，当注射到导水管周围灰质时，以CB 1依赖性方式增强应激诱导的镇痛作用。花生四烯酸失活酶脂肪酸酰胺水解酶（6）的抑制剂，选择性地提高花生四烯酸浓度，发挥类似的作用。我们的研究结果表明，协调释放的2-AG和花生四烯酸在中脑导水管周围灰质可能介导阿片类药物非依赖性应激镇痛。这些研究还确定单酰基甘油脂肪酶作为以前未被认识的治疗靶点。
Acute stress suppresses pain by activating brain pathways that engage opioid or non-opioid mechanisms. Here we show that an opioid-independent form of this phenomenon, termed stress-induced analgesia(1), is mediated by the release of endogenous marijuana-like (cannabinoid) compounds in the brain. Blockade of cannabinoid CB1 receptors in the periaqueductal grey matter of the midbrain prevents non-opioid stress-induced analgesia. In this region, stress elicits the rapid formation of two endogenous cannabinoids, the lipids 2-arachidonoylglycerol(2) (2-AG) and anandamide(3). A newly developed inhibitor of the 2-AG-deactivating enzyme, monoacylglycerol lipase(4,5), selectively increases 2-AG concentrations and, when injected into the periaqueductal grey matter, enhances stress-induced analgesia in a CB1-dependent manner. Inhibitors of the anandamide-deactivating enzyme fatty-acid amide hydrolase(6), which selectively elevate anandamide concentrations, exert similar effects. Our results indicate that the coordinated release of 2-AG and anandamide in the periaqueductal grey matter might mediate opioid-independent stress-induced analgesia. These studies also identify monoacylglycerol lipase as a previously unrecognized therapeutic target.