Several physiological functions of 2-arachido.noylglycerol; an endogenous cannabinoid receptor ligand

内源性大麻模拟分子2-花生四烯醇甘油通过大麻素CB2受体依赖机制诱导HL-60细胞内游离Ca^<2+>浓度的快速、短暂增加。我们检查了一些相关化合物（2-花生四烯醇甘油，其结构类似物和几种合成大麻素）的活性。我们发现2-花生四烯醇甘油是迄今为止检测到的最有效的化合物。这些结果强烈提示大麻素CB2受体最初是一个2-花生四烯醇甘油受体，2-花生四烯醇甘油是大麻素CB2受体的内在生理配体，已知其主要在免疫系统中表达。我们还发现，2-花生四烯醇甘油诱导了HL-60细胞中p42/p44 MAP激酶的激活，并增强了IL-8和MCP-1等kemokines的产生。这些结果强烈提示2-花生四烯醇甘油在免疫系统中是一个重要的介质。接下来，我们检测了注射微毒素的大鼠脑分离物中2-花生四烯醇甘油的水平。我们发现，注射微毒素后大鼠脑内2-花生四烯醇甘油水平明显升高。在无头大鼠脑中观察到类似的结果。这些结果表明，在刺激条件下，大脑中产生了大量的2-花生四烯醇甘油。我们证实，当C^<a2+>存在时，在大鼠脑浆液中迅速产生大量的2-花生四烯醇甘油，我们接下来检查了2-花生四烯醇甘油对血管系统的影响。我们发现2-花生四烯醇甘油可引起大鼠低血压。我们还发现2-花生四烯醇甘油能促进离体大鼠心脏去甲肾上腺素的释放。这些结果表明2-花生四烯醇甘油是一种可能的血管调节剂。

An endogenous cannabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca^<2+> concentrations in HL-60 cells through a cannabinoid CB2 receptor-dependent mechanism. We examined the activities of a number of relevant compounds (2-arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2-arachidonoylglycerol is the most potent compound examined so far. These results strongly suggested that the cannabinoid CB2 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic physiological ligand for the cannabinoid CB2 receptor which is known to be expressed mainly in the immune system. We also found that 2-arachidonoylglycerol induces the activation of p42/p44 MAP kinases and the enhanced production of kemokines such as IL-8 and MCP-1 in HL-60 cells. These results strongly suggest that 2-arachidonoylglycerol is an important mediator in the immune system, Next, we examined the level of 2-arachidonoylglycerol in the brain isolated from rats injected with picrotoxinin. We found that the level of 2-arachidonoylglycerol was augmented markedly in picrotoxinin-injected rat brain. Similar results were observed with decapitated rat brain. These results suggest that a substantial amount of 2-arachidonoylglycerol was produced in the brain under the condition of stimulation. We confirmed that a large amount of 2-arachidonoylglycerrol was generated rapidly in rat brain homogenate when incubated in the presence of C^<a2+>, We next examined the effect of 2-arachidonoylglycerol on the vascular system. We found that 2-arachidonoylglycerrol induces hypotension in rats. We also found that 2-arachidonoylglycerol enhanced norepinephrine release in isolated rat heart. These results suggest that 2-arachidonoylglycerol is a possible vasomodulator.