Danish Headache Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
Univ Rennes, Inserm, EHESP, Irset (Institut de recherche en santé, environnement et travail) - UMR_S 1085, Rennes, France.
Cephalalgia. 2021 Dec;41(14):1413-1426. doi: 10.1177/03331024211038884. Epub 2021 Aug 18.
Knowledge of exact signalling events during migraine attacks is lacking. Various substances are known to trigger migraine attacks in patients and calcitonin gene-related peptide antagonising drugs are effective against migraine pain. Here, we investigated the signalling pathways involved in three different mouse models of provoked migraine and relate them to calcitonin gene-related peptide and other migraine-relevant targets.
mouse models of glyceryl trinitrate-, cilostazol- and levcromakalim-induced migraine were applied utilising tactile sensitivity to von Frey filaments as measuring readout. Signalling pathways involved in the three models were dissected by use of specific knockout mice and chemical inhibitors. results were supported by wire myograph experiments measuring arterial dilatory responses and calcitonin gene-related peptide release from trigeminal ganglion and trigeminal nucleus caudalis from mice.
Glyceryl trinitrate-induced hypersensitivity was dependent on both prostaglandins and transient receptor potential cation channel, subfamily A, member 1, whereas cilostazol- and levcromakalim-induced hypersensitivity were independent of both. All three migraine triggers activated calcitonin gene-related peptide signalling, as both receptor antagonism and antibody neutralisation of calcitonin gene-related peptide were effective inhibitors of hypersensitivity in all three models. Stimulation of trigeminal ganglia and brain stem tissue samples with cilostazol and levcromakalim did not result in release of calcitonin gene-related peptide, and vasodilation following levcromakalim stimulation was independent of CGRP receptor antagonism.
The mouse models of glyceryl trinitrate-, cilostazol- and levcromakalim- induced migraine all involve calcitonin gene-related peptide signalling in a complex interplay between different cell/tissue types. These models are useful in the study of migraine mechanisms.
目前对于偏头痛发作时确切的信号事件知之甚少。已知各种物质可引发偏头痛患者的偏头痛发作，降钙素基因相关肽拮抗剂对偏头痛疼痛有效。在这里，我们研究了三种不同的诱发偏头痛小鼠模型中涉及的信号通路，并将其与降钙素基因相关肽和其他偏头痛相关靶点相关联。
利用 von Frey 纤维触觉敏感性作为测量读数，应用甘油三硝酸酯、西洛他唑和左西孟旦诱导的偏头痛小鼠模型。使用特定的基因敲除小鼠和化学抑制剂来剖析三种模型中涉及的信号通路。结果通过测量动脉扩张反应的电生理实验和来自小鼠三叉神经节和三叉神经尾核的降钙素基因相关肽释放得到支持。
甘油三硝酸酯诱导的过敏反应既依赖于前列腺素又依赖于瞬时受体电位阳离子通道亚家族 A 成员 1，而西洛他唑和左西孟旦诱导的过敏反应则与两者均无关。所有三种偏头痛触发物都激活了降钙素基因相关肽信号，因为降钙素基因相关肽受体拮抗剂和抗体中和降钙素基因相关肽在所有三种模型中都是过敏反应的有效抑制剂。西洛他唑和左西孟旦刺激三叉神经节和脑干组织样本不会导致降钙素基因相关肽的释放，而左西孟旦刺激后的血管扩张不依赖于 CGRP 受体拮抗剂。
甘油三硝酸酯、西洛他唑和左西孟旦诱导的偏头痛小鼠模型均涉及降钙素基因相关肽信号，涉及不同细胞/组织类型之间的复杂相互作用。这些模型可用于偏头痛机制的研究。
