Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres.
Sumatriptan inhibition of N-type calcium channel mediated signaling in dural CGRP terminal fibres.
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DOI：
10.1016/j.neuropharm.2012.04.016
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发表时间：
2012-09
影响因子：
4.7
通讯作者：
Mulligan SJ
中科院分区：
文献类型：
--
作者：
Baillie LD;Ahn AH;Mulligan SJ
选择性5-HT 1受体激动剂舒马曲坦是治疗偏头痛的有效药物，但其抗偏头痛的作用机制仍存在争议。广泛认为，密集支配硬脑膜的含有降钙素基因相关肽（CGRP）的疼痛反应纤维是偏头痛发生的重要解剖基质。硬脑膜中的5 HT 1受体与CGRP纤维以高密度共定位，从而为舒马曲坦提供了可能的外周作用位点。在本研究中，我们使用高分辨率的光学成像选择性地在个别小鼠硬脑膜CGRP伤害性纤维终端，并发现应用舒马曲坦引起一个快速的，可逆的剂量依赖性抑制幅度的单一动作电位诱发的Ca 2+瞬变。预先应用5-HT 1拮抗剂GR 127935或选择性5-HT 1D拮抗剂BRL 15572可阻止抑制作用，而选择性5-HT 1B拮抗剂SB 224289则不能，表明这种作用是通过5-HT 1D受体亚型选择性介导的。舒马曲普坦抑制动作电位诱发的Ca ~（2+）信号传导选择性地通过N型Ca ~（2+）通道介导。虽然T型Ca 2+通道占Ca 2+信号的更大比例，但它不介导任何舒马曲坦抑制。我们的研究结果支持舒马曲坦通过单一钙离子通道亚型选择性抑制硬脑膜疼痛纤维活性的外周作用位点。这一发现增加了我们对5 HT 1受体激动剂（如舒马曲坦）临床有效性机制的理解，并可能为开发新型外周靶向治疗药物减轻偏头痛疼痛提供见解。
The selective 5-HT1 receptor agonist sumatriptan is an effective therapeutic for migraine pain yet the antimigraine mechanisms of action remain controversial. Pain-responsive fibres containing calcitonin gene-related peptide (CGRP) densely innervating the cranial dura mater are widely believed to be an essential anatomical substrate for the development of migraine pain. 5HT1 receptors in the dura colocalize with CGRP fibres in high density and thus provide a possible peripheral site of action for sumatriptan. In the present study, we used high-resolution optical imaging selectively within individual mouse dural CGRP nociceptive fibre terminations and found that application of sumatriptan caused a rapid, reversible dose-dependent inhibition in the amplitude of single action potential evoked Ca2+ transients. Pre-application of the 5-HT1 antagonist GR127935 or the selective 5-HT1D antagonist BRL 15572 prevented inhibition while the selective 5-HT1B antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT1D receptor subtype. Sumatriptan inhibition of the action potential evoked Ca2+ signaling was mediated selectively through N-type Ca2+ channels. Although the T-type Ca2+ channel accounted for a greater proportion of the Ca2+ signal it did not mediate any of the sumatriptan inhibition. Our findings support a peripheral site of action for sumatriptan in inhibiting the activity of dural pain fibres selectively through a single Ca2+ channel subtype. This finding adds to our understanding of the mechanisms that underlie the clinical effectiveness of 5HT1 receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.
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影响因子：
11.2
作者：
Bartsch, T;Knight, YE;Goadsby, PJ
通讯作者：
Goadsby, PJ
影响因子：
3.3
作者：
Amrutkar, D. V.;Ploug, K. B.;Jansen-Olesen, I.
通讯作者：
Jansen-Olesen, I.
影响因子：
5.5
作者：
DODGE, FA;RAHAMIMO.R
通讯作者：
RAHAMIMO.R
影响因子：
6
作者：
Durham PL;Vause CV
通讯作者：
Vause CV
影响因子：
3
作者：
Baillie, Landon D.;Hagen, Volker;Mulligan, Sean J.
通讯作者：
Mulligan, Sean J.