Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice
Inhibition of FAAH reduces nitroglycerin-induced migraine-like pain and trigeminal neuronal hyperactivity in mice
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DOI：
10.1016/j.euroneuro.2015.04.001
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发表时间：
2015-08-01
影响因子：
5.6
通讯作者：
Zimmer, Andreas
中科院分区：
文献类型：
--
作者：
Nozaki, Chihiro;Markert, Astrid;Zimmer, Andreas
有证据表明，内源性大麻素信号的失调可能有助于偏头痛的病因和病理生理。因此，患有慢性偏头痛或药物滥用性头痛的患者表现出花生四烯酰基乙醇酰胺（AEA）降解酶脂肪酸酰胺水解酶（FAAH）和特定AEA膜转运蛋白活性的改变，以及AEA水平的变化。然而，不同内源性大麻素系统成分的确切作用尚不清楚。因此，我们在硝酸甘油诱导的偏头痛动物模型中研究了两种主要大麻素受体CBI和CB2基因缺失的小鼠，或主要内源性大麻素降解酶FAAH和单酰基甘油脂肪酶（MAGL），后者可降解2-花生四烯醇甘油（2-AG）。我们发现，硝酸甘油诱导的机械异常性疼痛和三叉神经核的神经元激活在faah缺陷小鼠中被完全消除。为了验证这些结果，我们使用了两种结构不同的FAAH抑制剂URB597和PF3945。这两种抑制剂也剂量依赖性阻断硝酸甘油诱导的痛觉过敏和三叉神经的激活。基因缺失对FAAH药理学阻断的影响是由CBI受体介导的，因为它们被CB1拮抗剂利莫那班完全破坏。这些结果确定FAAH是偏头痛药物治疗的靶点。(C) 2015 Elsevier B.V.和ECNP。版权所有。
There is evidence to suggest that a dysregulation of endocannabinoid signaling may contribute to the etiology and pathophysiology of migraine. Thus, patients suffering from chronic migraine or medication overuse headache showed alterations in the activity of the arachidonoylethanolamide (AEA) degrading enzyme fatty acid amide hydrolase (FAAH) and a specific AEA membrane transporter, alongside with changes in AEA levels. The precise role of different endocannabinoid system components is, however, not clear. We have therefore investigated mice with a genetic deletion of the two main cannabinoid receptors CBI and CB2, or the main endocannabinoid degrading enzymes, FAAH and monoacylglycerol lipase (MAGL), which degrades 2-arachidonoylglycerol (2-AG), in a nitroglycerine-induced animal model of migraine. We found that nitroglycerin-induced mechanical allodynia and neuronal activation of the trigeminal nucleus were completely abolished in FAAH-deficient mice. To validate these results, we used two structurally different FAAH inhibitors, URB597 and PF3945. Both inhibitors also dose-dependently blocked nitroglycerin-induced hyperalgesia and the activation of trigeminal neurons. The effects of the genetic deletion of pharmacological blockade of FAAH are mediated by CBI receptors, because they were completely disrupted with the CB1 antagonist rimonabant. These results identify FAAH as a target for migraine pharmacotherapy. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.