Targeting the Endocannabinoid System for Headache Intervention

针对内源性大麻素系统进行头痛干预

基本信息

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
项目类别：
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

项目摘要

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.

项目概要头痛影响着超过 3900 万美国人，但对细胞和分子机制的充分了解尚未实现潜在的病理性头痛；尚未发现新的、临床上有用的治疗方法。因此，本提案将使用补充技术来 1) 理解机械原理。内源性大麻素系统 (ECBS) 失调对头痛病理的影响，2) 验证增强 eCB 基调的治疗策略将提供比当前治疗方法更好的选择。使用两种雄性大鼠头痛、皮质扩散性抑郁（CSD）和药物过度使用（MOH）模型和雌性大鼠以确定 ECBS 在头痛中发挥的细胞和分子作用。最近的临床观察支持临床内源性大麻素缺乏症（CED）作为潜在疾病的观点然而，研究为 eCB 在治疗偏头痛中的机制作用提供了证据。初步数据表明，皮质 KCl 和药物过度使用都会消耗 2AG 和增加 PAG 的炎症，PAG 是与下行疼痛调节有关的中脑区域。雌性大鼠多于雄性大鼠，2AG 药物消耗可诱发头痛症状这些令人兴奋的发现进一步支持了头痛中 eCB 音调的丧失是性别选择性的。假设头痛是由于 PAG 中 2AG 的性别依赖性增强降解所致 ABHD6 和 MAGL 导致炎症增加和导致疼痛的下行抑制丧失三个目标将定义 ABHD6 作为 2AG 逆行可用性“看门人”的角色。释放（目标 1）；确定 MAGL 在头痛期间终止 2-AG 作用的作用，这可能有助于维持（目标 2）；并确定 PAG 内的 ECBS 失调如何在男性和女性中发生头痛等疼痛的诱导、维持和恢复过程中的分子和细胞水平（目标 3）。目标之间的这些结果的整合将清楚地描述 2-AG 在 PAG 中的作用头痛诱导和维持，并通过针对 MAGL 和/或 ABHD6 验证增加的 eCB 音调作为偏头痛治疗的独特新目标，该项目的成功完成将为偏头痛治疗提供基础。选择性地针对 ECBS 进行偏头痛干预启动药物发现计划的基本原理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。