Brain Circuits of Migraine Pain

偏头痛的大脑回路

• 批准号: 10710388
• 负责人: Edita Navratilova
• 金额: $ 62.11万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10710388
• 关键词: Acute; Address; Affect; Affective; Agonist; Agreement; Amygdaloid structure; Antibodies; Antibody Therapy; Area; Behavior; Bilateral; Blood - brain barrier anatomy; Brain; Brain region; CRISPR/Cas technology; Calcitonin Gene-Related Peptide; Calcitonin-Gene Related Peptide Receptor; Calcium; Cell Nucleus; Cells; Cephalic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Development; Disease; Dorsal; Dura Mater; Electrophysiology (science); Emotional; Fc Receptor; Female; Fiber; Fright; Functional disorder; Genetic; Glutamates; Human; Ibotenic Acid; Image; Inflammation Mediators; Knowledge; Lesion; Link; Measures; Mediating; Meningeal; Meninges; Methods; Microscopy; Migraine; Modeling; Mus; Neurons; Nociception; Nociceptors; Organism; Output; Pain; Pathology; Pathway interactions; Patients; Peptides; Peripheral; Persons; Pharmaceutical Preparations; Phase; Pontine structure; Preventive; Preventive treatment; Quality of life; Role; Severities; Signal Transduction; Site; Slice; Structure; Synapses; Trigeminal Pain; Trigeminal System; Visceral; allodynia; antagonist; behavioral outcome; behavioral response; cell type; coping; cranium; experience; genetic manipulation; human imaging; imaging study; improved; male; migraine treatment; nervous system disorder; neural; neuroimaging; optogenetics; pain behavior; parabrachial nucleus; pharmacologic; pre-clinical; preclinical study; prevent; redshift; response; sensory input; small molecule; therapy development; transmission process

Summary Migraine is a prevalent neurological disorder affecting millions of people worldwide. The underlying pathophysiology of migraine likely involves diverse mechanisms within the trigeminal pain pathways and pain- related structures in the brain. Recently introduced medications targeting CGRP mechanisms including antibodies and small molecule CGRP receptor antagonists appear to act outside of the blood brain barrier. These medications are effective as preventive treatment in some patients implicating the role of meningeal CGRP in migraine pathology. However, many patients do not respond to these therapies and even those that do often experience “breakthrough migraines” suggesting the existence of non-CGRP peripheral migraine mechanisms. The brain circuits mediating migraine pain remain understudied. Cephalic nociceptive pathways involve activation of trigeminal afferents and transmission of the nociceptive signal through the second order cells in the trigeminocervical complex (TCC) to multiple brain regions. Human neuroimaging studies during a migraine attack have demonstrated activations in the amygdala and dorsal pons, encompassing the parabrachial nucleus (PBN). The PBN receives both exteroceptive and interoceptive sensory inputs and projects to multiple sites including the central nucleus of the amygdala (CeA), an area mediating emotional aspects of pain. Our preclinical studies using pharmacological and optogenetic activation of dural afferents, neuronal tracing and behavior suggest a functional pathway from the dura mater to TCC, PBN and CeA that may promote migraine-like pain. In this proposal, we will use opto/chemo-genetic methods, microscopy with immunostaining and RNAscope, CRISPR-Cas9 (i.e., CRISPR) genetic manipulations, electrophysiology, calcium imaging and pain behavior to investigate if, and how, the PBN→CeA pathway may promote migraine-like pain elicited by activation of dural afferents using several different approaches in male and female mice. Aim 1 will measure the effects on markers of neural activation in brain networks (microscopy) and consequences on pain behavior; Aim 2 will use brain slice electrophysiology and calcium imaging with pharmacological, CRISPR or opto/chemo-genetic manipulations of PBN outputs to evaluate plasticity of CeA cell types; Aim 3 will use chemogenetic inhibition of PBN outputs or CRISPR deletions in the CeA to evaluate possible inhibition of migraine pain behaviors. Our studies aim to address significant gaps in our knowledge of central pathways of migraine pain. We will determine the potential relevance of the central PBN→CeA circuit as a common pathway of migraine pain that can be engaged by CGRP-dependent and CGRP-independent peripheral mechanisms.

概括 偏头痛是一种流行的神经系统疾病，影响了全球数百万的人。基础 偏头痛的病理生理可能涉及三叉神经疼痛途径内的不同机制和疼痛 大脑中的相关结构。最近引入了针对CGRP机制的药物 抗体和小分子CGRP受体拮抗剂似乎在血脑屏障之外起作用。这些 药物在某些患者中作为预防治疗有效，隐含脑膜CGRP在 偏头痛病理学。但是，许多患者对这些疗法也没有反应 体验“突破性偏头痛”，表明存在非CGRP外围偏头痛机制。 介导偏头痛疼痛的大脑电路仍然了解。头部伤害感受途径涉及 三叉神经传入的激活和伤害性信号通过二阶细胞的传播 到多个大脑区域的三角形复合物（TCC）。偏头痛攻击期间的人类神经影像学研究 已经在杏仁核和背侧脑PON中表现出激活，其中包括副核（PBN）。 PBN接收到外观感受和跨感受的感官输入和项目，包括 杏仁核（CEA）的中央核，这是一个介导疼痛情绪方面的区域。我们的临床前研究 使用硬脑膜传入的药物和光遗传学激活，神经元跟踪和行为表明 从硬脑膜到TCC，PBN和CEA的功能途径可能会促进偏头痛样疼痛。 在此提案中，我们将使用OPT/化学基因方法，具有免疫染色的显微镜和rnascope， CRISPR-CAS9（即CRISPR）遗传操纵，电生理学，钙成像和疼痛行为 调查PBN→CEA途径是否以及如何促进偏头痛的疼痛来激活硬脑膜的疼痛 在雄性和雌性小鼠中使用几种不同方法的传入。 AIM 1将衡量对标记的影响 脑网络中的神经激活（显微镜）和对疼痛行为的后果； AIM 2将使用大脑 用药物，CRISPR或OPT/Chemo-Genetic进行切片电生理学和钙成像 对PBN输出的操纵以评估CEA细胞类型的可塑性； AIM 3将使用化学生成抑制 CEA中的PBN输出或CRISPR缺失，以评估偏头痛疼痛行为的抑制。 我们的研究旨在解决我们对偏头痛疼痛中心途径的了解的巨大差距。我们将 确定中央PBN→CEA电路的潜在相关性，作为偏头痛疼痛的常见途径 可以由CGRP依赖性和与CGRP无关的外围机制参与。