The role of Peripheral CGRP in a preclinical mouse model of migraine

项目摘要/摘要 偏头痛是一种复杂的、令人衰弱的神经疾病，涉及神经肽降钙素基因- 相关肽(CGRP)。该项目的总体目标是确定通过哪些外围设备 CGRP会导致畏光，这是一种对非有害水平的光线的痛苦反应，约90%的人经历过 偏头痛患者。外周注射CGRP会引起光厌恶，这种反应类似于 恐光症。在野生型中的这种反应需要明亮的光线，而在全球转基因小鼠中 CGRP受体增加即使在昏暗的光线下也能看到增强的反应。有趣的是，这 神经系统升高的转基因小鼠中未见增强的避光表型 受体的表达。这一证据表明，外周注射降钙素基因相关肽可能导致 厌恶和激活神经通路的间接机制。由于降钙素基因相关肽是最有效的 体内的血管扩张剂，我们假设降钙素基因相关肽可以通过血管机制引起光厌恶。 这一假说是基于以下发现：1)人体内静脉注射降钙素基因相关肽可以 引起偏头痛；2)血管周围降钙素基因相关肽可使三叉神经敏化，从而改变 突触传递到中枢神经系统。因此，存在着一种机制，通过这种机制， 外周可以使三叉神经敏感，改变感官知觉，导致畏光。单人间 目的是确定血管系统在避光行为中的作用。 将使用互补的药理和遗传策略。药理学方法将是 联合应用血管收缩药以最大限度地减少降钙素基因相关肽引起的血管扩张。遗传方法将是 血管内皮细胞和血管内皮细胞条件过表达CGRP受体转基因小鼠的建立 血管系统的肌肉细胞。这一目标将使我们深入了解外设 CGRP可以在偏头痛的临床前小鼠模型中引发类似偏头痛的症状。

Project Summary/Abstract Migraine is a complex and debilitating neurological disorder involving the neuropeptide calcitonin gene- related peptide (CGRP). The overall objective of this project is to identify mechanisms by which peripheral CGRP causes photophobia, a painful response to non-noxious levels of light experienced by ~90% of migraine patients. Peripheral injection of CGRP causes light aversion, a response analogous to photophobia. This response in wild-type requires bright light, while in transgenic mice with globally increased CGRP receptors there is an enhanced response seen even in dim light. Interestingly, this enhanced light aversive phenotype is not seen in transgenic mice that have elevated nervous system expression of the receptor. This evidence suggests that peripheral CGRP administration may cause light aversion and activate neural pathways in an indirect mechanism. Since CGRP is one of the most potent vasodilators in the body, we hypothesize that CGRP can cause light aversion by a vascular mechanism. This hypothesis is based on findings that 1) intravenous administration of CGRP in human subjects can cause migraine pain, and 2) perivascular CGRP can sensitize the trigeminal nerve, which could alter synaptic transmission to the central nervous system. Thus, there is a mechanism by which CGRP in the periphery can sensitize the trigeminal nerve and alter sensory perception, leading to photophobia. A single aim is proposed that will establish the contribution of the vasculature in light aversive behavior. Complementary pharmacological and genetic strategies will be used. The pharmacological approach will be to co-administer a vasoconstrictor to minimize CGRP-induced vasodilation. The genetic approach will be to generate transgenic mice with conditional overexpression of CGRP receptors on endothelial and smooth muscle cells of the vasculature. This aim will provide insight into the mechanisms by which peripheral CGRP can trigger a migraine-like symptom in a preclinical mouse model of migraine.