Department of Physiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
Neuropharmacology. 2012 Sep;63(3):362-7. doi: 10.1016/j.neuropharm.2012.04.016.
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. 5-HT₁ 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 GR 127935 or the selective 5-HT(1D) antagonist BRL 15572 prevented inhibition while the selective 5-HT(1B) antagonist SB 224289 did not, suggesting this effect was mediated selectively through the 5-HT(1D) 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 5-HT₁ receptor agonists such as sumatriptan and may provide insight for the development of novel peripherally targeted therapeutics for mitigating the pain of migraine.
选择性 5-HT₁ 受体激动剂舒马曲坦是治疗偏头痛疼痛的有效药物，但 5-HT₁ 受体激动剂的作用机制仍存在争议。含有降钙素基因相关肽 (CGRP) 的痛觉纤维密集地支配颅顶硬膜，被广泛认为是偏头痛疼痛发展的重要解剖学基础。硬膜中的 5-HT₁ 受体与 CGRP 纤维高密度共定位，因此为舒马曲坦提供了一个可能的外周作用部位。在本研究中，我们使用高分辨率光学成像选择性地在单个小鼠硬脑膜 CGRP 伤害性纤维末端内进行研究，发现舒马曲坦的应用会导致单个动作电位诱发的 Ca²⁺瞬变幅度的快速、可逆、剂量依赖性抑制。5-HT₁ 拮抗剂 GR 127935 或选择性 5-HT(1D)拮抗剂 BRL 15572 的预先应用可防止抑制，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。舒马曲坦对动作电位诱发的 Ca²⁺信号的抑制作用是通过 N 型 Ca²⁺ 通道选择性介导的。虽然 T 型 Ca²⁺ 通道占 Ca²⁺ 信号的比例更大，但它并不介导舒马曲坦的任何抑制作用。我们的发现支持舒马曲坦在抑制硬脑膜痛纤维活性方面的外周作用部位，通过单一 Ca²⁺ 通道亚型选择性地发挥作用。这一发现增加了我们对 5-HT₁ 受体激动剂（如舒马曲坦）临床疗效的作用机制的理解，并可能为开发新型外周靶向治疗偏头痛疼痛提供思路。
