Modulation of CGRP-Induced Light Aversion in Wild-Type Mice by a 5-HT1B/D Agonist
Modulation of CGRP-Induced Light Aversion in Wild-Type Mice by a 5-HT1B/D Agonist
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DOI：
10.1523/jneurosci.3265-12.2012
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发表时间：
2012-10-31
影响因子：
5.3
通讯作者：
Russo, Andrew F.
中科院分区：
文献类型：
--
作者：
Kaiser, Eric A.;Kuburas, Adisa;Russo, Andrew F.
神经肽降钙素基因相关肽（CGRP）在偏头痛的病理生理学中起着至关重要的作用。我们关注CGRP在偏头痛中的作用，这是一种常见的偏头痛症状。我们以前使用了一个基于操作的测定表明，CGRP致敏的转基因（巢蛋白/hRAMP 1），但不是控制，小鼠表现出光厌恶反应脑室内CGRP注射。一个关键问题是转基因表型是否是由于内源性或新的表达位点的CGRP受体的过度表达。我们推断，如果内源性受体位点对于光厌恶行为是足够的，那么野生型小鼠在给予足够强的刺激时也应该表现出表型。在这项研究中，我们报告说，小鼠与正常水平的内源性CGRP受体表现出避光后CGRP管理。这种表型需要两个因素的结合：更高的光强度和对测试室的适应。对照试验证实，光厌恶依赖于同时暴露于CGRP和光，不能完全解释为焦虑增加。此外，CGRP只在黑暗中减少运动，而不是在光中。同时给予5-HT 1B/D激动剂抗偏头痛药物利扎曲普坦可减弱外源性CGRP对光厌恶和运动的影响。这表明曲坦类药物可以通过与抑制CGRP释放不同的机制起作用。因此，我们证明内源性CGRP受体的激活足以引起小鼠的光厌恶，这可以通过通常用于治疗偏头痛的药物来调节。
The neuropeptide calcitonin gene-related peptide (CGRP) plays a critical role in the pathophysiology of migraine. We have focused on the role of CGRP in photophobia, which is a common migraine symptom. We previously used an operant-based assay to show that CGRP-sensitized transgenic (nestin/hRAMP1), but not control, mice exhibited light aversion in response to an intracerebroventricular CGRP injection. A key question was whether the transgenic phenotype was due to overexpression of the CGRP receptor at endogenous or novel expression sites. We reasoned that if endogenous receptor sites were sufficient for light-aversive behavior, then wild-type mice should also show the phenotype when given a sufficiently strong stimulus. In this study, we report that mice with normal levels of endogenous CGRP receptors demonstrate light avoidance following CGRP administration. This phenotype required the combination of two factors: higher light intensity and habituation to the testing chamber. Control tests confirmed that light aversion was dependent on coincident exposure to CGRP and light and cannot be fully explained by increased anxiety. Furthermore, CGRP reduced locomotion only in the dark, not in the light. Coadministration of rizatriptan, a 5-HT1B/D agonist anti-migraine drug, attenuated the effects of exogenous CGRP on light aversion and motility. This suggests that triptans can act by mechanisms that are distinct from inhibition of CGRP release. Thus, we demonstrate that activation of endogenous CGRP receptors is sufficient to elicit light aversion in mice, which can be modulated by a drug commonly used to treat migraine.