Possible inhibitory role of endogenous 2-arachidonoylglycerol as an endocannabinoid in (±)-epibatidine-induced activation of central adrenomedullary outflow in the rat.
Possible inhibitory role of endogenous 2-arachidonoylglycerol as an endocannabinoid in (±)-epibatidine-induced activation of central adrenomedullary outflow in the rat.
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内源性 2-花生四烯酰甘油作为内源性大麻素在 (±)-epibatidine 诱导的大鼠中枢肾上腺髓质流出激活中可能具有抑制作用。
DOI：
10.1016/j.neuropharm.2015.03.034
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发表时间：
2015
影响因子：
4.7
通讯作者：
Saito M
中科院分区：
文献类型：
--
作者：
Shimizu T;Tanaka K;Shimizu S;Higashi Y;Yawata T;Nakamura K;Taniuchi K;Ueba T;Yuri K;Saito M
我们以前报道，脑室（i. c. v.）给予（±）-地棘蛙素（1、5或10 nmol/动物），一种烟碱乙酰胆碱受体激动剂，通过脑二酰基甘油脂肪酶（DGL）、单酰基甘油脂肪酶（MGL）和环加氧酶介导的机制，剂量依赖性地诱导大鼠肾上腺髓质分泌去甲肾上腺素和肾上腺素（儿茶酚胺）。甘油二酯被DGL水解为2-花生四烯酸酰甘油（2-AG），2-AG进一步被MGL水解为花生四烯酸（AA），一种环氧合酶底物。这些结果表明，脑2-AG-衍生的AA参与（±）-epibatidine诱导的反应。这种AA前体2-AG也是一种主要的脑内源性大麻素，其通过突触前大麻素CB 1受体抑制突触传递。释放到突触间隙中的2-AG被细胞摄取迅速灭活。在这里，我们研究了大脑2-AG作为内源性大麻素在（±）-epibatidine诱导的中枢肾上腺髓质流出激活麻醉雄性Wistar大鼠的作用。在中枢存在AM 251（CB 1拮抗剂）（90和180 nmol/动物，i. c. v.）的情况下，即使在无效剂量（1 nmol/动物，i. c. v.）下，（±）-地棘蛙素也可升高血浆儿茶酚胺。ACEA（CB 1激动剂）（0.7和1.4 μmol/动物，i. c. v.）中枢预处理，2-AG醚（MGL的稳定2-AG类似物）（0.5和1.0 μmol/动物，i. c. v.）或AM404（内源性大麻素摄取抑制剂）（80和250 nmol/动物，i. c. v.）显著降低了（±）-地棘蛙素-（5 nmol/动物，i. c. v.）诱导血浆儿茶酚胺升高，AM 251（90和180 nmol/动物，i. c. v.）中枢性阻断2-AG乙醚（1.0 μmol/只动物，i. c. v.）或AM404（250 nmol/动物，i. c. v.）。免疫组织化学研究表明，（±）-地棘蛙素（10 nmol/动物，i. c. v.）激活中枢肾上腺髓质系统的控制中枢下丘脑室旁核DGLα阳性脊髓投射神经元。这些结果表明，脑内源性大麻素，可能2-AG，在（±）-epibatidine诱导的激活中枢肾上腺髓质流出通过脑CB 1受体在大鼠中发挥抑制作用的可能性。
We previously reported that intracerebroventricularly (i.c.v.) administered (±)-epibatidine (1, 5 or 10 nmol/animal), a nicotinic acetylcholine receptor agonist, dose-dependently induced secretion of noradrenaline and adrenaline (catecholamines) from the rat adrenal medulla by brain diacylglycerol lipase- (DGL), monoacylglycerol lipase- (MGL) and cyclooxygenase-mediated mechanisms. Diacylglycerol is hydrolyzed by DGL into 2-arachidonoylglycerol (2-AG), which is further hydrolyzed by MGL to arachidonic acid (AA), a cyclooxygenase substrate. These findings suggest that brain 2-AG-derived AA is involved in the (±)-epibatidine-induced response. This AA precursor 2-AG is also a major brain endocannabinoid, which inhibits synaptic transmission through presynaptic cannabinoid CB1receptors. Released 2-AG into the synaptic cleft is rapidly inactivated by cellular uptake. Here, we examined a role of brain 2-AG as an endocannabinoid in the (±)-epibatidine-induced activation of central adrenomedullary outflow using anesthetized male Wistar rats. In central presence of AM251 (CB1antagonist) (90 and 180 nmol/animal, i.c.v.), (±)-epibatidine elevated plasma catecholamines even at an ineffective dose (1 nmol/animal, i.c.v.). Central pretreatment with ACEA (CB1agonist) (0.7 and 1.4 μmol/animal, i.c.v.), 2-AG ether (stable 2-AG analog for MGL) (0.5 and 1.0 μmol/animal, i.c.v.) or AM404 (endocannabinoid uptake inhibitor) (80 and 250 nmol/animal, i.c.v.) significantly reduced an effective dose of (±)-epibatidine- (5 nmol/animal, i.c.v.) induced elevation of plasma catecholamines, and AM251 (90 and 180 nmol/animal, i.c.v.) centrally abolished the reduction induced by 2-AG ether (1.0 μmol/animal, i.c.v.) or AM404 (250 nmol/animal, i.c.v.). Immunohistochemical studies demonstrated that (±)-epibatidine (10 nmol/animal, i.c.v.) activated DGLα-positive spinally projecting neurons in the hypothalamic paraventricular nucleus, a control center of central adrenomedullary system. These results suggest a possibility that a brain endocannabinoid, probably 2-AG, plays an inhibitory role in (±)-epibatidine-induced activation of central adrenomedullary outflow through brain CB1receptors in the rat.