Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, IRCCS Mondino Foundation Pavia, Italy.
Laboratory of Neurophysiology of Integrative Autonomic Systems, Headache Science Centre, IRCCS Mondino Foundation Pavia, Italy.
Neurobiol Dis. 2020 Feb;134:104624. doi: 10.1016/j.nbd.2019.104624. Epub 2019 Oct 17.
Fatty-acid amide hydrolase (FAAH) is an intracellular serine hydrolase that catalyzes the cleavage of endogenous fatty-acid amides, including the endocannabinoid anandamide (AEA). We previously reported that the peripherally restricted FAAH inhibitor URB937, which selectively increases AEA levels outside the central nervous system, reduces hyperalgesia and c-Fos expression in the trigeminal nucleus caudalis (TNC) and the locus coeruleus in an animal model of migraine based on nitroglycerin (NTG) administration.
To further investigate the relevance of FAAH inhibition in the NTG animal model of migraine by testing the effects of the globally active FAAH inhibitor URB597.
Our experimental approach involved mapping neuronal c-Fos protein expression, measurement of AEA levels in brain areas and in trigeminal ganglia, evaluation of pain-related behavior and quantification of molecular mediators in rats that received URB597 (2 mg/kg i.p.) either before or after NTG administration (10 mg/kg, i.p.).
Pre-treatment with URB597 significantly reduced c-Fos immunoreactivity in the TNC and inhibited NTG-induced hyperalgesia in the orofacial formalin test. This behavioral response was associated with a decrease in neuronal nitric oxide synthase, calcitonin gene-related peptide and cytokine gene expression levels in central and peripheral structures. Administration of URB597 after NTG had no such effect.
The findings suggest that global FAAH inhibition may offer a therapeutic approach to the prevention, but not the abortive treatment, of migraine attacks. Further studies are needed to elucidate the exact cellular and molecular mechanisms underlying the protective effects of FAAH inhibition.
脂肪酸酰胺水解酶（FAAH）是一种细胞内丝氨酸水解酶，可催化内源性脂肪酸酰胺的裂解，包括内源性大麻素大麻素（AEA）。我们之前报道过，外周受限的 FAAH 抑制剂 URB937 选择性地增加中枢神经系统外的 AEA 水平，可减少偏头痛动物模型中硝酸甘油（NTG）给药引起的三叉神经尾核（TNC）和蓝斑核中痛觉过敏和 c-Fos 表达。
通过测试全局活性 FAAH 抑制剂 URB597，进一步研究 FAAH 抑制在偏头痛 NTG 动物模型中的相关性。
我们的实验方法包括映射神经元 c-Fos 蛋白表达，测量大脑区域和三叉神经节中的 AEA 水平，评估疼痛相关行为，并在接受 URB597（2mg/kg ip）预处理或 NTG 给药后（10mg/kg，ip）的大鼠中定量分子介质。
URB597 预处理显著降低了 TNC 中的 c-Fos 免疫反应性，并抑制了 NTG 诱导的口腔福尔马林试验中的痛觉过敏。这种行为反应与中央和外周结构中神经元一氧化氮合酶、降钙素基因相关肽和细胞因子基因表达水平的降低有关。在 NTG 后给予 URB597 则没有这种作用。
这些发现表明，全球 FAAH 抑制可能是预防偏头痛发作的一种治疗方法，但不是偏头痛发作的中止治疗。需要进一步研究阐明 FAAH 抑制的保护作用的确切细胞和分子机制。
