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.

项目总结 头痛影响着3900多万美国人，但对细胞和分子的全面了解 头痛的病理基础尚未实现；新的、临床有用的治疗方法的发现是 因此是有限的。这项提议将使用互补的技术来1)理解 内源性大麻素系统(ECBS)失调在头痛病理中的作用和2)验证 治疗策略，增强欧洲央行的语气，提供比当前治疗方法更好的选择。研究将会 在雄性使用两种大鼠头痛模型，皮质扩散性抑制(CSD)和药物过度使用(MOH) 和雌性大鼠，以确定ECB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(CED)是一种潜在的 偏头痛在某些患者中的作用机制；然而，为ECB在偏头痛中的机制作用提供证据的研究 偏头痛是有限的。初步数据表明，皮质氯化钾和药物过度使用都会消耗2AG和 增加PAG的炎症，这是一个与下行疼痛调制有关的中脑区域。此外， 2AG的药理耗竭可导致更多雌性大鼠出现头痛症状 进一步支持以性别选择性的方式在头痛中失去欧洲央行的语气。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 ABHD6和MAGL导致炎症增加和导致疼痛的下行抑制丧失 行为。三个目标将定义ABHD6作为2AG逆行可用性的“看门人”的角色 释放(Aim1)；确定MAGL在终止头痛期间可能起作用的2-AG活动中的作用 维持(目标2)；并确定ECB如何在PAG内发生男性和女性在 头痛样疼痛诱导、维持和恢复过程中的分子和细胞水平(目标3)。 这些结果在AIMS之间的整合将清楚地描述2-AG在PAG中的作用 令人头痛的诱导和维护，并通过针对MAGL和/或ABHD6验证ECB语气的提高 作为偏头痛治疗的独特新靶点。该项目的成功完成将为 启动有选择地针对偏头痛干预的ECB的药物发现计划的理由 与目前的治疗方法相比，这是治疗头痛的更好的临床选择。