Possible inhibitory roles of endogenous 2-arachidonoylglycerol during corticotropin-releasing factor-induced activation of central sympatho-adrenomedullary outflow in anesthetized rats.
Possible inhibitory roles of endogenous 2-arachidonoylglycerol during corticotropin-releasing factor-induced activation of central sympatho-adrenomedullary outflow in anesthetized rats.
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DOI：
10.1016/j.ejphar.2010.05.007
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发表时间：
2010-09
影响因子：
5
通讯作者：
Takahiro Shimizu;Lianyi Lu;K. Yokotani
中科院分区：
文献类型：
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作者：
Takahiro Shimizu;Lianyi Lu;K. Yokotani
我们以前报道，脑室（i. c. v.）给大鼠注射促肾上腺皮质激素释放因子（CRF）（0.5-3.0nmol/只）可通过脑磷脂酶C、二酰基甘油脂肪酶和前列腺素介导的机制剂量依赖性地升高血浆去甲肾上腺素和肾上腺素。由磷脂酶C从磷脂产生的二酰基甘油可以被二酰基甘油脂肪酶水解成2-花生四烯酸，其可以被单酰基甘油脂肪酶进一步水解成花生四烯酸，前列腺素类的前体。最近，2-花生四烯酸甘油被认为是一种主要的脑内源性大麻素，它可以通过突触前大麻素CB 1受体调节突触传递。释放的2-花生四烯酰甘油通过摄入细胞和酶水解而迅速失活。因此，在本研究中，我们使用麻醉大鼠研究了（1）脑2-花生四烯酸甘油的参与，（2）2-花生四烯酸甘油作为脑内源性大麻素的调节作用，以及（3）外源性大麻素受体激动剂对CRF诱导的血浆去甲肾上腺素和肾上腺素升高的影响。次大剂量CRF（1.5nmol/只，i. c. v.）通过i. c. v.给药MAFP（单酰甘油脂肪酶抑制剂）（0.7和1.4μmol/动物）、AM 404（内源性大麻素摄取抑制剂）（80和250 nmol/动物）和ACEA（大麻素CB 1受体激动剂）（0.7和1.4μmol/动物），而AM 251（大麻素CB 1受体拮抗剂）（90和180 nmol/动物，i. c. v.）增强小剂量CRF（0.5nmol/只）引起的反应。这些结果表明，2-花生四烯酸甘油是内源性产生的脑CRF诱导的激活中枢交感神经-肾上腺髓质流出，从而抑制肽诱导的反应，激活麻醉大鼠脑大麻素CB 1受体的可能性。
We previously reported that intracerebroventricularly (i.c.v.) administered corticotropin-releasing factor (CRF) (0.5–3.0nmol/animal) dose-dependently elevates plasma noradrenaline and adrenaline through brain phospholipase C-, diacylglycerol lipase- and prostanoids-mediated mechanisms in rats. Diacylglycerol produced by phospholipase C from phospholipids can be hydrolyzed by diacylglycerol lipase into 2-arachidonoylglycerol, which may be further hydrolyzed by monoacylglycerol lipase into arachidonic acid, a precursor of prostanoids. Recently, 2-arachidonoylglycerol has been recognized as a major brain endocannabinoid, which can modulate synaptic transmission through presynaptic cannabinoid CB1receptors. Released 2-arachidonoylglycerol is rapidly deactivated by uptake into cells and enzymatic hydrolysis. In the present study, therefore, we examined (1) the involvement of brain 2-arachidonoylglycerol, (2) the regulatory role of 2-arachidonoylglycerol as a brain endocannabinoid, and (3) the effect of exogenous cannabinoid receptor agonist, on the CRF-induced elevation of plasma noradrenaline and adrenaline using anesthetized rats. The elevation of both catecholamines induced by a submaximal dose of CRF (1.5nmol/animal, i.c.v.) was reduced by i.c.v. administered MAFP (monoacylglycerol lipase inhibitor) (0.7 and 1.4µmol/animal), AM 404 (endocannabinoid uptake-inhibitor) (80 and 250nmol/animal) and ACEA (cannabinoid CB1receptor agonist) (0.7 and 1.4µmol/animal), while AM 251 (cannabinoid CB1receptor antagonist) (90 and 180nmol/animal, i.c.v.) potentiated the response induced by a small dose of CRF (0.5nmol/animal, i.c.v.). These results suggest a possibility that 2-arachidonoylglycerol is endogenously generated in the brain during CRF-induced activation of central sympatho-adrenomedullary outflow, thereby inhibiting the peptide-induced response by activation of brain cannabinoid CB1receptors in anesthetized rats.