Calcitonin gene-related peptide (CGRP), substance P and dural mast cells are main contributors in neurogenic inflammation underlying migraine pathophysiology. Modulation of endocannabinoid system attenuates migraine pain, but its mechanisms of action remain unclear. We investigated receptor mechanisms mediating anti-neuroinflammatory effects of endocannabinoid system modulation in in vivo migraine model and ex vivo hemiskull preparations in rats. To induce acute model of migraine, a single dose of nitroglycerin was intraperitoneally administered to male rats. Moreover, isolated ex vivo rat hemiskulls were prepared to study CGRP and substance P release from meningeal trigeminal afferents. We used methanandamide (cannabinoid agonist), rimonabant (cannabinoid receptor-1 CB1 antagonist), SR144528 (CB2 antagonist) and capsazepine (transient receptor potential vanilloid-1 TRPV1 antagonist) to explore effects of endocannabinoid system modulation on the neurogenic inflammation, and possible involvement of CB1, CB2 and TRPV1 receptors during endocannabinoid effects. Methanandamide attenuated nitroglycerin-induced CGRP increments in in vivo plasma, trigeminal ganglia and brainstem and also in ex vivo hemiskull preparations. Methanandamide also alleviated enhanced number and degranulation of dural mast cells induced by nitroglycerin. Rimonabant, but not capsazepine or SR144528, reversed the attenuating effects of methanandamide on CGRP release in both in vivo and ex vivo experiments. Additionally, SR144528, but not rimonabant or capsazepine, reversed the attenuating effects of methanandamide on dural mast cells. However, neither nitroglycerin nor methanandamide changed substance P levels in both in vivo and ex vivo experiments. Methanandamide modulates CGRP release in migraine-related structures via CB1 receptors and inhibits the degranulation of dural mast cells through CB2 receptors. Selective ligands targeting CB1 and CB2 receptors may provide novel and effective treatment strategies against migraine.

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受体机制介导内源性大麻素系统调节在偏头痛大鼠模型中的抗神经炎症作用

降钙素基因相关肽 (CGRP)、P 物质和硬脑膜肥大细胞是偏头痛病理生理学神经源性炎症的主要贡献者。内源性大麻素系统的调节可减轻偏头痛，但其作用机制仍不清楚。我们研究了介导体内偏头痛模型和大鼠离体半颅制剂中内源性大麻素系统调节的抗神经炎症作用的受体机制。为了诱导偏头痛的急性模型，向雄性大鼠腹膜内施用单剂量的硝酸甘油。此外，制备了分离的离体大鼠半颅骨来研究脑膜三叉神经传入的 CGRP 和 P 物质释放。我们使用了甲南酰胺（大麻素激动剂）、利莫那班（大麻素受体 1 CB1 拮抗剂）、SR144528（CB2 拮抗剂）和 capsazepine（瞬时受体电位 vanilloid-1 TRPV1 拮抗剂）探索内源性大麻素系统调节对神经源性炎症的影响，以及 CB1、CB2 和 TRPV1 受体在内源性大麻素作用期间的可能参与。Methanandamide 减弱了体内血浆、三叉神经节和脑干以及体外半颅骨制剂中硝酸甘油诱导的 CGRP 增加。Methanandamide 还减轻了由硝酸甘油诱导的硬脑膜肥大细胞数量增加和脱粒。Rimonabant，但不是 capsazepine 或 SR144528，在体内和体外实验中逆转了甲南酰胺对 CGRP 释放的减弱作用。此外，SR144528（而非利莫那班或卡西平）逆转了甲南酰胺对硬脑膜肥大细胞的减毒作用。然而，在体内和体外实验中，硝酸甘油和甲南酰胺都没有改变 P 物质的水平。Methanandamide 通过 CB1 受体调节偏头痛相关结构中的 CGRP 释放，并通过 CB2 受体抑制硬脑膜肥大细胞的脱颗粒。靶向 CB1 和 CB2 受体的选择性配体可提供针对偏头痛的新型有效治疗策略。