Department of Neural and Pain Sciences, Dental School, University of Maryland, Baltimore, Maryland 21201, USA.
J Neurosci. 2010 Jun 9;30(23):7878-88. doi: 10.1523/JNEUROSCI.6053-09.2010.
Migraineurs experience debilitating headaches that result from neurogenic inflammation of the dura and subsequent sensitization of dural afferents. Given the importance of inflammatory mediator (IM)-induced dural afferent sensitization to this pain syndrome, the present study was designed to identify ionic mechanisms underlying this process. Trigeminal ganglion neurons from adult female Sprague Dawley rats were acutely dissociated 10-14 d after application of retrograde tracer DiI onto the dura. Modulation of ion channels and changes in excitability were measured in the absence and presence of IMs (in mum: 1 prostaglandin, 10 bradykinin, and 1 histamine) using whole-cell and perforated-patch recordings. Fura-2 was used to assess changes in intracellular Ca(2+). IMs modulated a number of currents in dural afferents, including those both expected and/or previously described [i.e., an increase in tetrodotoxin-resistant voltage-gated Na(+) current (TTX-R I(Na)) and a decrease in voltage-gated Ca(2+) current] as well currents never before described in sensory neurons (i.e., a decrease in a Ca(2+)-dependent K(+) current and an increase in a Cl(-) current), and produced a sustained elevation in intracellular Ca(2+). Although several of these currents, in particular TTX-R I(Na), appear to contribute to the sensitization of dural afferents, the Cl(-) current is the primary mechanism underlying this process. Activation of this current plays a dominant role in the sensitization of dural afferents because of the combination of the density and biophysical properties of TTX-R I(Na), and the high level of intracellular Cl(-) in these neurons. These results suggest novel targets for the development of antimigraine agents.
偏头痛患者会经历由硬脑膜神经源性炎症和随后的硬脑膜传入纤维敏化引起的使人虚弱的头痛。鉴于炎性介质 (IM) 诱导的硬脑膜传入纤维敏化对这种疼痛综合征的重要性，本研究旨在确定该过程的离子机制。成年雌性 Sprague Dawley 大鼠的三叉神经节神经元在逆行示踪剂 DiI 施加到硬脑膜后 10-14 天被急性分离。使用全细胞和穿孔贴片记录，在不存在和存在 IM（在 mum 中：1 前列腺素、10 缓激肽和 1 组胺）的情况下测量离子通道的调制和兴奋性变化。使用 Fura-2 评估细胞内 Ca(2+)的变化。IM 调节了硬脑膜传入纤维中的许多电流，包括预期的和/或以前描述的电流（即增加河豚毒素抗性电压门控 Na(+)电流（TTX-R I(Na)) 和减少电压门控 Ca(2+)电流）以及以前在感觉神经元中从未描述过的电流（即减少 Ca(2+)依赖性 K(+)电流和增加 Cl(-)电流），并产生持续的细胞内 Ca(2+)升高。尽管这些电流中的几种，特别是 TTX-R I(Na)，似乎有助于硬脑膜传入纤维的敏化，但 Cl(-)电流是该过程的主要机制。由于 TTX-R I(Na)的密度和生物物理特性以及这些神经元中细胞内 Cl(-)的高水平，该电流的激活在硬脑膜传入纤维的敏化中起着主导作用。这些结果为开发抗偏头痛药物提供了新的靶点。
