Targeting the Endocannabinoid System for Headache Intervention

针对内源性大麻素系统进行头痛干预

• 批准号: 10584948
• 负责人: Tally Marie Milnes
• 金额: $ 64.09万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10584948
• 关键词: 2-arachidonylglycerol; ABHD6 gene; Affect; American; Analgesic Overuse Headaches; Attenuated; Behavioral; CNR1 gene; CNR2 gene; Clinical; Coupled; Data; Detection; Diglycerides; Dinoprostone; Endocannabinoids; Enzymes; Face; Female; Foundations; Gatekeeping; Glial Fibrillary Acidic Protein; Gliosis; Headache; High Prevalence; Hydrolysis; Inflammation; Injections; Intervention; Knowledge; Lipids; MAGL inhibitor; Maintenance; Midbrain structure; Migraine; Modeling; Molecular; Molecular Biology; Neurons; Outcome Measure; Pain; Pathology; Patients; Pharmaceutical Preparations; Play; Preclinical Testing; Prevention; Proteins; Proteomics; Publishing; Rattus; Recovery; Regulation; Role; Signal Transduction; Solid; Spreading Cortical Depression; Symptoms; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Work; allodynia; anandamide; behavioral outcome; cellular pathology; drug discovery; endocannabinoid signaling; endogenous cannabinoid system; enzyme activity; immunocytochemistry; improved; inhibitor; male; midbrain central gray substance; migraine treatment; molecular pathology; neurotransmitter release; novel; pain behavior; pharmacologic; postsynaptic; presynaptic; prevent; programs; receptor; sex; therapeutic target; trend

PROJECT SUMMARY Headache affects more than 39 million Americans, yet a full understanding of the cellular and molecular pathology underlying headache has not been achieved; the discovery of novel, clinically useful therapeutics is therefore limited. This proposal will use complimentary techniques to 1) understand the mechanistic contributions of endocannabinoid system (ECBS) dysregulation to headache pathology and 2) validate a therapeutic strategy that enhances eCB tone to offer an improved option over current therapeutics. Studies will use two rat models of headache, cortical spreading depression (CSD) and medication-overuse (MOH) in male and female rats to define the cellular and molecular role played by the ECBS in headache. Recent clinical observations support the idea of Clinical Endocannabinoid Deficiency (CED) as a potential mechanism of migraine in some patients; however, studies providing evidence for a mechanistic role of eCBs in migraine are limited. Preliminary data suggest that both cortical KCl and medication overuse deplete 2AG and increase inflammation in the PAG, a midbrain region implicated in descending pain modulation. Further, headache symptomology could be induced by pharmacological depletion of 2AG in more female than male rats further supporting loss of eCB tone in headache in a sex-selective manner. These exciting findings led to the hypothesis that headache pain results from sex-dependent enhanced degradation of 2AG in the PAG by ABHD6 and MAGL leading to increased inflammation and loss of descending inhibition that drive pain behaviors. Three Aims will define the role of ABHD6 as the “gatekeeper” of 2AG availability for retrograde release (Aim1); determine the role of MAGL in terminating 2-AG actions during headache which may contribute to maintenance (Aim 2); and establish how ECBS dysregulation within the PAG occurs in males and females at the molecular and cellular levels during induction, maintenance, and recovery from headache like pain (Aim 3). Integration of these results between aims will clearly delineate the role of 2-AG within the PAG plays a role in headache induction and maintenance and validate increasing eCB tone by targeting either MAGL and/or ABHD6 as unique new targets for migraine therapy. Successful completion of this project will provide foundational rationale to initiate a drug discovery program selectively targeting the ECBS for migraine intervention to provide a better clinical option against headache as compared to current therapeutics.

项目摘要 头痛影响超过3900万美国人，但对细胞和分子的充分了解 头痛的病理学基础尚未实现;新的、临床上有用的治疗方法的发现， 因此有限。本提案将使用补充技术来1）理解 内源性大麻素系统（ECBS）失调对头痛病理学的贡献; 2）验证了 增强eCB张力的治疗策略，以提供优于当前疗法的改进选择。研究将 采用皮质扩散性抑制（CSD）和药物过度使用（MOH）两种大鼠头痛模型 和雌性大鼠，以确定ECBS在头痛中所起的细胞和分子作用。 最近的临床观察支持临床内源性大麻素缺乏症（CED）作为一种潜在的 一些患者的偏头痛机制;然而，研究提供了eCB在偏头痛中的机制作用的证据， 偏头痛是有限的。初步数据表明，皮质KCl和药物过度使用都会消耗2AG， 增加PAG中的炎症，PAG是与下行疼痛调制有关的中脑区域。此外，本发明还 在雌性大鼠中，2AG的药理学消耗可诱导比雄性大鼠更多的头痛病理学改变 进一步支持头痛中eCB张力以性别选择性方式丧失。这些令人兴奋的发现导致了 假设头痛是由PAG中2AG的性别依赖性增强降解引起的， ABHD 6和MAGL导致炎症增加和驱动疼痛的下行抑制的丧失 行为。三个目标将定义ABHD 6作为2AG逆行可用性的“看门人”的角色 释放（Aim 1）;确定MAGL在头痛期间终止2-AG作用的作用， 维持（目标2）;并确定PAG内的ECBS失调如何发生在男性和女性中， 在头痛样疼痛的诱导、维持和恢复过程中的分子和细胞水平（目的3）。 将这些结果整合在目标之间将清楚地描述2-AG在PAG中的作用， 通过靶向MAGL和/或ABHD诱导和维持头痛并验证eCB张力增加6 作为治疗偏头痛的独特新靶点。该项目的成功完成将为 启动选择性靶向ECBS治疗偏头痛的药物发现计划的理由， 与目前的治疗方法相比，这是一种更好的治疗头痛的临床选择。