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; 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，但对细胞和分子有充分的了解 尚未实现基础标头的病理；新颖，临床上有用的疗法的发现是 因此有限。该建议将使用免费技术来1）了解机械 内源性大麻素系统（ECB）失调对标题病理学的贡献和2）验证 可以增强欧洲央行张力的治疗策略，以比当前的治疗剂提供改进的选择。研究将 在男性中使用两种大鼠标题，皮质扩散抑郁症（CSD）和药物弥补（MOH） 雌性大鼠定义了ECB在标题中扮演的细胞和分子作用。 最近的临床观察结果支持临床内源性大麻素缺乏症（CED）的想法 一些患者的偏头痛机制；但是，研究提供了ECB在机械作用中的证据 偏头痛有限。初步数据表明，皮质KCL和药物过度使用重复2ag和 增加PAG的炎症，PAG是一个在降低疼痛调节中实施的中脑区域。更远， 与雄性大鼠相比，女性多2AG的药理学耗竭可以诱导头痛症状。 进一步支持以性选择性方式在标题中丧失欧洲央行音调。这些令人兴奋的发现导致了 假设标题疼痛是由于性别依赖性增强了PAG中2AG的降解而引起的。 ABHD6和MAGL导致感染增加和降低抑制作用的损失 行为。三个目标将定义ABHD6的作用为2ag可用性的“守门人” 释放（AIM1）;确定MAGL在终止标头过程中终止2 AG动作的作用，这可能有助于 维护（目标2）；并确定在PAG内的ECB失调如何发生在男性和女性中 在诱导，维持和从标头等疼痛等恢复过程中的分子和细胞水平（AIM 3）。 在目标之间的这些结果的集成将清楚地描述PAG中2-ag的作用 通过靶向MAGL和/或ABHD6，头痛诱导和维护以及验证欧洲央行的增加 作为偏头痛治疗的独特新目标。该项目的成功完成将提供基础 启动药物发现计划的理由选择性针对ECB的偏头痛干预措施以提供 与当前疗法相比，针对标头的更好的临床选择。