Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.
Selective spider toxins reveal a role for the Nav1.1 channel in mechanical pain.
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DOI：
10.1038/nature17976
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发表时间：
2016-06-23
期刊：
影响因子：
64.8
通讯作者：
Julius D
中科院分区：
文献类型：
--
作者：
Osteen JD;Herzig V;Gilchrist J;Emrick JJ;Zhang C;Wang X;Castro J;Garcia-Caraballo S;Grundy L;Rychkov GY;Weyer AD;Dekan Z;Undheim EA;Alewood P;Stucky CL;Brierley SM;Basbaum AI;Bosmans F;King GF;Julius D
电压门控钠(NAV)通道在大多数神经元上启动动作电位，包括痛觉通路的初级传入神经纤维。局麻药通过在所有NAV通道上的非特异性作用来阻断疼痛，但选择性调节剂的发现将有助于分析个别亚型及其对化学、机械或热痛的贡献。在这里，我们识别和表征了选择性激活Nav1.1亚型的蜘蛛毒素，其在伤害性感受和疼痛中的作用尚未被探索。我们利用这些探针来证明Nav1.1表达的纤维是通道特异性的伤害性感受器：它们的激活引起强烈的疼痛行为，而不是神经源性炎症，并对机械刺激而不是热刺激产生深刻的超敏反应。在肠道中，高阈值机械敏感纤维也表达Nav1.1，并在肠易激综合征模型中显示出增强的毒素敏感性。总之，这些发现确立了Nav1.1在调节作为机械性疼痛基础的感觉神经纤维的兴奋性方面的意想不到的作用。
Voltage-gated sodium (Nav) channels initiate action potentials in most neurons, including primary afferent nerve fibers of the pain pathway. Local anesthetics block pain through non-specific actions at all Nav channels, but the discovery of selective modulators would facilitate the analysis of individual subtypes and their contributions to chemical, mechanical, or thermal pain. Here, we identify and characterize spider toxins that selectively activate the Nav1.1 subtype, whose role in nociception and pain has not been explored. We exploit these probes to demonstrate that Nav1.1-expressing fibers are modality-specific nociceptors: their activation elicits robust pain behaviors without neurogenic inflammation and produces profound hypersensitivity to mechanical, but not thermal, stimuli. In the gut, high-threshold mechanosensitive fibers also express Nav1.1 and show enhanced toxin sensitivity in a model of irritable bowel syndrome. Altogether, these findings establish an unexpected role for Nav1.1 in regulating the excitability of sensory nerve fibers that underlie mechanical pain.