BACKGROUND Recently, the adenosine triphosphate (ATP) sensitive potassium channel opener levcromakalim was shown to induce migraine attacks with a far higher incidence than any previous provoking agent such as calcitonin gene-related peptide. Here, we show efficacy of ATP sensitive potassium channel inhibitors in two validated rodent models of migraine. METHODS In female spontaneous trigeminal allodynic rats, the sensitivity of the frontal region of the head was tested by an electronic von Frey filament device. In mice, cutaneous hypersensitivity was induced by repeated glyceryl trinitrate or levcromakalim injections over nine days, as measured with von Frey filaments in the hindpaw. Release of calcitonin gene-related peptide from dura mater and trigeminal ganglion was studied ex vivo. RESULTS The ATP sensitive potassium channel inhibitor glibenclamide attenuated the spontaneous cephalic hypersensitivity in spontaneous trigeminal allodynic rats and glyceryl trinitrate-induced hypersensitivity of the hindpaw in mice. It also inhibited CGRP release from dura mater and the trigeminal ganglion isolated from spontaneous trigeminal allodynic rats. The hypersensitivity was also diminished by the structurally different ATP sensitive potassium channel inhibitor gliquidone. Mice injected with the ATP sensitive potassium channel opener levcromakalim developed a progressive hypersensitivity that was completely blocked by glibenclamide, confirming target engagement. CONCLUSION The results suggest that ATP sensitive potassium channel inhibitors could be novel and highly effective drugs in the treatment of migraine.

中文翻译：

---

ATP 敏感钾 (KATP) 通道抑制：一种有前景的偏头痛新药靶点。

背景最近，三磷酸腺苷 (ATP) 敏感的钾通道开放剂 levcromakalim 显示出诱发偏头痛发作的发生率远高于任何先前的诱发剂，例如降钙素基因相关肽。在这里，我们展示了 ATP 敏感钾通道抑制剂在两种经过验证的偏头痛啮齿动物模型中的功效。方法在雌性自发性三叉神经异常性疼痛大鼠中，通过电子 von Frey 灯丝装置测试头部额区的敏感性。在小鼠中，通过在 9 天内重复注射三硝酸甘油酯或左旋卡林可诱导皮肤超敏反应，如后爪中的 von Frey 细丝所测量。体外研究了从硬脑膜和三叉神经节释放降钙素基因相关肽。结果 ATP 敏感性钾通道抑制剂格列本脲减弱了自发性三叉神经异常性疼痛大鼠的自发性头部超敏反应和三硝酸甘油酯诱导的小鼠后爪超敏反应。它还抑制从自发性三叉神经异常性疼痛大鼠分离的硬脑膜和三叉神经节释放 CGRP。结构不同的 ATP 敏感钾通道抑制剂格列喹酮也降低了超敏反应。注射了 ATP 敏感钾通道开放剂 levcromakalim 的小鼠出现了渐进性超敏反应，该超敏反应被格列本脲完全阻断，证实了靶点参与。结论 ATP敏感性钾通道抑制剂可能是治疗偏头痛的新型高效药物。