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。我们集中于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员的测定法来显示CGRP致敏的转基因小鼠(nestin / hRAMP1)而非对照小鼠表现出对脑室内CGRP注射的反感。一个关键问题是转基因表型是否是由于内源或新表达位点上CGRP受体的过度表达所致。我们认为,如果内源性受体位点足以进行光平均行为,那么当给予足够强的刺激时,野生型小鼠也应表现出表型。在这项研究中,我们报告内源性CGRP受体水平正常的小鼠在CGRP给药后表现出避光作用。该表型需要两个因素的结合:较高的光强度和对测试室的适应性。对照测试证实,厌恶光取决于同时接触CGRP和光照,不能通过焦虑增加充分解释。此外,CGRP仅在黑暗中而不是在光线下减少运动。利扎曲普坦(5-HT(1B / D)激动剂抗偏头痛药物)的共同给药减弱了外源性CGRP对避光和运动的影响。这表明曲普坦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受体的激活足以在小鼠中引起避光,这可以通过通常用于治疗偏头痛的药物进行调节。

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