Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6).
Sensitization of dural afferents underlies migraine-related behavior following meningeal application of interleukin-6 (IL-6).
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DOI：
10.1186/1744-8069-8-6
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发表时间：
2012-01-24
期刊：
影响因子：
3.3
通讯作者：
Dussor G
中科院分区：
文献类型：
--
作者：
Yan J;Melemedjian OK;Price TJ;Dussor G
偏头痛是最常见的神经系统疾病之一，但导致偏头痛的病理生理机制知之甚少。颅内白细胞介素-6（IL-6）水平已被证明在偏头痛发作期间升高，这表明这种细胞因子可能促进来自脑膜的疼痛信号，并有助于头痛的发展。在用IL-6单独或与MEK抑制剂U 0126组合刺激硬脑膜后，在大鼠中测量皮肤异常性疼痛。采用膜片钳电生理技术，在逆行标记的硬脑膜传入纤维上测量斜坡电流刺激下的动作电位数目和第一个动作电位峰的潜伏期以及电流阈值。这些记录是在IL-6单独或与U 0126组合存在下进行的。还通过免疫共沉淀测量IL-6处理后ERK 1和Nav1.7之间的关联。在这里，我们报告说，在清醒的动物，直接应用IL-6的硬脑膜产生剂量依赖性的面部和后爪异常性疼痛。MEK抑制剂U 0126阻断IL-6诱导的异常性疼痛，表明IL-6通过MAP激酶途径产生这种行为效应。在从硬脑膜逆行标记的三叉神经元中，IL-6的应用降低了动作电位放电的电流阈值。响应于斜坡电流刺激，用IL-6处理的细胞显示出动作电位数量的增加和第一个尖峰的潜伏期的减少，这一效应与钠通道Nav1.7的磷酸化一致。用U 0126预处理逆转IL-6处理后的过度兴奋。此外，免疫共沉淀实验表明IL-6处理后ERK 1和Nav1.7之间的关联增加。我们的研究结果表明，IL-6可能通过ERK介导的Nav1.7调节增强硬脑膜传入神经的兴奋性，这些反应有助于体内偏头痛相关的疼痛行为。这些数据提供了一种细胞机制，通过该机制脑膜中的IL-6引起硬脑膜传入神经的敏化，从而有助于偏头痛的发病机制。
Migraine headache is one of the most common neurological disorders, but the pathophysiology contributing to migraine is poorly understood. Intracranial interleukin-6 (IL-6) levels have been shown to be elevated during migraine attacks, suggesting that this cytokine may facilitate pain signaling from the meninges and contribute to the development of headache. Cutaneous allodynia was measured in rats following stimulation of the dura with IL-6 alone or in combination with the MEK inhibitor, U0126. The number of action potentials and latency to the first action potential peak in response to a ramp current stimulus as well as current threshold were measured in retrogradely-labeled dural afferents using patch-clamp electrophysiology. These recordings were performed in the presence of IL-6 alone or in combination with U0126. Association between ERK1 and Nav1.7 following IL-6 treatment was also measured by co-immunoprecipitation. Here we report that in awake animals, direct application of IL-6 to the dura produced dose-dependent facial and hindpaw allodynia. The MEK inhibitor U0126 blocked IL-6-induced allodynia indicating that IL-6 produced this behavioral effect through the MAP kinase pathway. In trigeminal neurons retrogradely labeled from the dura, IL-6 application decreased the current threshold for action potential firing. In response to a ramp current stimulus, cells treated with IL-6 showed an increase in the numbers of action potentials and a decrease in latency to the first spike, an effect consistent with phosphorylation of the sodium channel Nav1.7. Pretreatment with U0126 reversed hyperexcitability following IL-6 treatment. Moreover, co-immunoprecipitation experiments demonstrated an increased association between ERK1 and Nav1.7 following IL-6 treatment. Our results indicate that IL-6 enhances the excitability of dural afferents likely via ERK-mediated modulation of Nav1.7 and these responses contribute to migraine-related pain behavior in vivo. These data provide a cellular mechanism by which IL-6 in the meninges causes sensitization of dural afferents therefore contributing to the pathogenesis of migraine headache.
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影响因子：
2.9
作者：
Rozniecki, JJ;Dimitriadou, V;Theoharides, TC
通讯作者：
Theoharides, TC
影响因子：
11.2
作者：
Edelmayer, Rebecca M.;Vanderah, Todd W.;Majuta, Lisa;Zhang, En-Tan;Fioravanti, Beatriz;De Felice, Milena;Chichorro, Juliana G.;Ossipov, Michael H.;King, Tamara;Lai, Josephine;Kori, Shashi H.;Nelsen, Andrew C.;Cannon, Keri E.;Heinricher, Mary M.;Porreca, Frank
通讯作者：
Porreca, Frank
影响因子：
1.7
作者：
Bao, L;Zhu, Y;Lindgren, JU
通讯作者：
Lindgren, JU
影响因子：
9.9
作者：
Bigal, M. E.;Ashina, S.;Lipton, R. B.
通讯作者：
Lipton, R. B.
DOI：
10.1016/s0169-328x(98)00257-5
发表时间：
1998-11-20
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
Arruda, JL;Colburn, RW;DeLeo, JA
通讯作者：
DeLeo, JA