Danish Headache Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Denmark.
Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark.
Cephalalgia. 2022 Feb;42(2):93-107. doi: 10.1177/03331024211053570. Epub 2021 Nov 24.
Opening of K channels by systemic levcromakalim treatment triggers attacks in migraine patients and hypersensitivity to von Frey stimulation in a mouse model. Blocking of these channels is effective in several preclinical migraine models. It is unknown in what tissue and cell type K-induced migraine attacks are initiated and which K channel subtype is targeted.
In mouse models, we administered levcromakalim intracerebroventricularly, intraperitoneally and intraplantarily and compared the nociceptive responses by von Frey and hotplate tests. Mice with a conditional loss-of-function mutation in the smooth muscle K channel subunit Kir6.1 were given levcromakalim and GTN and examined with von Frey filaments. Arteries were tested for their ability to dilate . mRNA expression, western blotting and immunohistochemical stainings were made to identify relevant target tissue for migraine induced by K channel opening.
Systemic administration of levcromakalim induced hypersensitivity but central and local administration provided antinociception respectively no effect. The Kir6.1 smooth muscle knockout mouse was protected from both GTN and levcromakalim induced hypersensitivity, and their arteries had impaired dilatory response to the latter. mRNA and protein expression studies showed that trigeminal ganglia did not have significant K channel expression of any subtype, whereas brain arteries and dura mater primarily expressed the Kir6.1 + SUR2B subtype.
Hypersensitivity provoked by GTN and levcromakalim in mice is dependent on functional smooth muscle K channels of extracerebral origin. These results suggest a vascular contribution to hypersensitivity induced by migraine triggers.
全身性给予 levcromakalim 可通过打开 K 通道引发偏头痛患者发作，并在小鼠模型中对 von Frey 刺激产生超敏反应。这些通道的阻断在几种临床前偏头痛模型中是有效的。尚不清楚 K 诱导的偏头痛发作是在什么组织和细胞类型中引发的，以及靶向哪种 K 通道亚型。
在小鼠模型中，我们通过脑室内、腹膜内和皮下给予 levcromakalim，并通过 von Frey 和热板试验比较疼痛反应。给予平滑肌 K 通道亚基 Kir6.1 条件性功能丧失突变的小鼠给予 levcromakalim 和 GTN，并通过 von Frey 纤维进行检查。测试动脉扩张能力。进行 mRNA 表达、western blot 和免疫组织化学染色，以确定由 K 通道开放引起的偏头痛的相关靶组织。
全身性给予 levcromakalim 可诱导超敏反应，但中枢和局部给予则分别提供镇痛作用。Kir6.1 平滑肌敲除小鼠对 GTN 和 levcromakalim 诱导的超敏反应均有保护作用，其动脉对后者的扩张反应受损。mRNA 和蛋白表达研究表明，三叉神经节没有任何亚型的显著 K 通道表达，而脑动脉和硬脑膜主要表达 Kir6.1+SUR2B 亚型。
在小鼠中，GTN 和 levcromakalim 引起的超敏反应依赖于脑外功能性平滑肌 K 通道。这些结果提示血管参与偏头痛触发物引起的超敏反应。
