University of Maryland, MD, USA.
Cephalalgia. 2012 Jul;32(10):738-49. doi: 10.1177/0333102412451356. Epub 2012 Jun 18.
To test the hypothesis that the clinical efficacy of triptans reflects convergent modulation of ion channels also involved in inflammatory mediator (IM)-induced sensitization of dural afferents.
Acutely dissociated retrogradely labeled rat dural afferents were studied with whole cell and perforated patch techniques in the absence and presence of sumatriptan and/or IM (prostaglandin E2, bradykinin, and histamine).
Sumatriptan dose-dependently suppressed voltage-gated Ca²⁺ currents. Acute (2 min) sumatriptan application increased dural afferent excitability and occluded further IM-induced sensitization. In contrast, pre-incubation (30 min) with sumatriptan had no influence on dural afferent excitability and partially prevented IM-induced sensitization of dural afferents. The sumatriptan-induced suppression of voltage-gated Ca²⁺ currents and acute sensitization and pre-incubation-induced block of IM-induced sensitization were blocked by the 5-HT(1D) antagonist BRL 15572. Pre-incubation with sumatriptan failed to suppress the IM-induced decrease in action potential threshold and overshoot (which results from modulation of voltage-gated Na⁺ currents) and activation of Cl⁻ current, and had no influence on the Cl⁻ reversal potential. However, pre-incubation with sumatriptan caused a dramatic hyperpolarizing shift in the voltage dependence of K⁺ current activation.
These results indicate that although the actions of sumatriptan on dural afferents are complex, at least two distinct mechanisms underlie the antinociceptive actions of this compound. One of these mechanisms, the shift in the voltage dependence of K⁺ channel activation, may suggest a novel strategy for future development of anti-migraine agents.
验证这样一个假设，即曲坦类药物的临床疗效反映了对离子通道的趋同调节，离子通道也参与了致炎介质（IM）诱导的硬脑膜传入纤维敏化。
采用全细胞膜片钳和穿孔膜片钳技术，在无和有舒马曲坦和/或 IM（前列腺素 E2、缓激肽和组胺）的情况下，对急性分离的逆行标记的大鼠硬脑膜传入纤维进行研究。
舒马曲坦呈剂量依赖性地抑制电压门控 Ca²⁺电流。急性（2 分钟）舒马曲坦应用增加硬脑膜传入纤维兴奋性，并阻断进一步的 IM 诱导的敏化。相比之下，预孵育（30 分钟）舒马曲坦对硬脑膜传入纤维兴奋性没有影响，并部分防止了 IM 诱导的硬脑膜传入纤维敏化。舒马曲坦诱导的电压门控 Ca²⁺电流抑制、急性敏化以及预孵育诱导的阻断 IM 诱导的敏化，均被 5-HT1D 拮抗剂 BRL 15572 阻断。预孵育舒马曲坦未能抑制 IM 诱导的动作电位阈值和超射（由电压门控 Na⁺电流调制引起）以及 Cl⁻电流的减少，并且对 Cl⁻反转电位没有影响。然而，预孵育舒马曲坦导致 K⁺电流激活的电压依赖性发生显著超极化偏移。
这些结果表明，尽管舒马曲坦对硬脑膜传入纤维的作用很复杂，但这种化合物的镇痛作用至少有两种不同的机制。其中一种机制，即 K⁺通道激活的电压依赖性偏移，可能为未来抗偏头痛药物的开发提供新策略。
