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-HT(1B/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.

译文

神经肽降钙素基因相关肽 (CGRP) 在偏头痛的病理生理中起关键作用。我们关注CGRP在畏光中的作用,这是一种常见的偏头痛症状。我们以前使用基于操作的测定法来显示CGRP致敏的转基因 (nestin/hRAMP1),但不是对照,小鼠对脑室内CGRP注射表现出光厌恶。一个关键问题是转基因表型是否归因于CGRP受体在内源性或新型表达位点的过表达。我们认为,如果内源性受体位点足以引起光厌恶行为,那么当给予足够强的刺激时,野生型小鼠也应显示出表型。在这项研究中,我们报告了具有正常水平的内源性CGRP受体的小鼠在CGRP给药后表现出避免光的作用。这种表型需要两个因素的结合: 更高的光强度和测试室的习惯。对照测试证实,光厌恶取决于同时暴露于CGRP和光,不能用焦虑增加来完全解释。此外,CGRP仅在黑暗中而不是在光线中减少运动。利扎曲普坦是一种5-HT(1B/D) 激动剂抗偏头痛药物,可减轻外源性CGRP对光厌恶和运动的影响。这表明曲坦类药物可以通过不同于抑制CGRP释放的机制起作用。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。

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