Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice
Behavioral evidence for photophobia and stress-related ipsilateral head pain in transgenic Cacna1a mutant mice
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DOI：
10.1016/j.pain.2013.03.038
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发表时间：
2013-08-01
期刊：
影响因子：
7.4
通讯作者：
Mogil, Jeffrey S.
中科院分区：
文献类型：
--
作者：
Chanda, Mona Lisa;Tuttle, Alexander H.;Mogil, Jeffrey S.
偏头痛是一种高度流行、致残和复杂的发作性脑疾病，其发病机制尚不清楚，部分原因是缺乏有效的动物模型。在这里，我们报告了在携带人类家族性偏瘫性偏头痛1型（FHM-1）的转基因敲入小鼠中标志性偏头痛特征的行为证据，即在编码Ca（V）2.1钙通道α（1）亚基的Cacna 1a基因中的功能获得性错义突变（R192 Q或S218 L）。使用改良的高架十字迷宫证明了畏光症，其中安全的闭合臂被明亮地照亮;突变小鼠避免了光，尽管在标准（焦虑）版本的测试中没有显示出差异。在192 Q突变体中发现了提示自发性头痛的多种行为措施，这些突变体受到新奇和/或约束压力。这些行为是：（1）突变型小鼠与野生型小鼠相比更常见;（2）突变型小鼠偏侧化，但野生型小鼠不偏侧化;（3）雌性小鼠与雄性小鼠相比更常见;以及（4）通过全身给予2种不同的急性镇痛药（利扎曲普坦和吗啡）而剂量依赖性正常化。此外，发现其中一些行为在218 L中比192 Q突变体更频繁和严重，与人类的临床表现一致。我们认为Cacna 1a转基因小鼠可以经历偏头痛相关的头痛，因此可以作为研究偏头痛发病机制和测试新型抗偏头痛药物的独特工具。(C)2013年国际疼痛研究协会。Elsevier B. V.出版，保留所有权利。
Migraine is a highly prevalent, disabling and complex episodic brain disorder whose pathogenesis is poorly understood, due in part to the lack of valid animal models. Here we report behavioral evidence of hallmark migraine features, photophobia and unilateral head pain, in transgenic knock-in mice bearing human familial hemiplegic migraine, type 1 (FHM-1) gain-of-function missense mutations (R192Q or S218L) in the Cacna1a gene encoding the Ca(V)2.1 calcium channel alpha(1) subunit. Photophobia was demonstrated using a modified elevated plus maze in which the safe closed arms were brightly illuminated; mutant mice avoided the light despite showing no differences in the standard (anxiety) version of the test. Multiple behavioral measures suggestive of spontaneous head pain were found in 192Q mutants subjected to novelty and/or restraint stress. These behaviors were: (1) more frequent in mutant versus wildtype mice; (2) lateralized in mutant but not in wildtype mice; (3) more frequent in females versus males; and (4) dose-dependently normalized by systemic administration of 2 different acute analgesics, rizatriptan and morphine. Furthermore, some of these behaviors were found to be more frequent and severe in 218L compared to 192Q mutants, consistent with the clinical presentation in humans. We suggest that Cacna1a transgenic mice can experience migraine-related head pain and can thus serve as unique tools to study the pathogenesis of migraine and test novel antimigraine agents. (C) 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.