Endocannabinoid Metabolism in Acute Pain

急性疼痛中的内源性大麻素代谢

• 批准号: 9886570
• 负责人: Martin Kaczocha
• 金额: $ 46.11万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-15 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9886570
• 关键词: 2-arachidonylglycerol; Absence of pain sensation; Acute; Acute Pain; Afferent Neurons; Anabolism; Analgesics; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Attenuated; Cells; Centers for Disease Control and Prevention (U.S.); Clinical; Complement; Coupled; Cyclooxygenase Inhibitors; Development; Dinoprostone; Eicosanoids; Endocannabinoids; Enzymes; Epidermis; Failure; Foundations; Human; Hydrolysis; Hydroxyeicosatetraenoic Acids; Immune; Knockout Mice; Knowledge; LOX gene; Lead; Ligands; MAGL inhibitor; Measures; Mediating; Medical; Metabolism; Modeling; Monoacylglycerol Lipases; Morphine; Mus; Operative Surgical Procedures; Opiate Addiction; Opioid; Outcome; Outcome Study; Oxycodone; Pain; Pain management; Pathway interactions; Patient-Focused Outcomes; Patients; Perioperative; Peripheral; Pharmacology; Population; Postoperative Pain; Postoperative Period; Prescription drug overdose; Prevalence; Productivity; Property; Prostaglandin-Endoperoxide Synthase; Publications; Receptor Activation; Reporting; Risk; Rodent; Role; Sampling; Site; Skin; Surgical Models; Surgical incisions; Testing; Tissues; Translations; United States; Vicodin; Work; addiction; behavior measurement; cannabinoid receptor; cell type; chronic neuropathic pain; chronic pain; cyclooxygenase 1; endogenous cannabinoid system; experimental study; genetic approach; human tissue; improved; inflammatory pain; inhibitor/antagonist; insight; keratinocyte; knee replacement arthroplasty; non-opioid analgesic; novel; opioid abuse; opioid sparing; opioid use; pre-clinical

Project Summary Failure to adequately treat pain accounts for hundreds of billions of dollars of lost productivity and medical expenses annually. According to the Centers for Disease Control, each day in the United States over forty people die from an overdose of prescription pain killers (e.g. Vicodin and OxyContin). Consequently, there is an urgent need to develop new, safe, and potent non-opioid analgesics for the treatment of acute and chronic pain. Many surgical procedures induce significant acute pain that is difficult to treat. Patients who undergo such major surgical procedures are also at an increased risk of developing a subsequent opioid addiction. Therefore, improving acute pain control will not only enhance patient outcomes but may also lead to reduced prevalence of subsequent opioid abuse. The endocannabinoid 2-arachidonoylglycerol (2-AG) produces analgesia by activating cannabinoid receptors. However, 2-AG can also be hydrolyzed by the enzyme monoacylglycerol lipase (MAGL) to generate arachidonic acid, the precursor to downstream eicosanoids that can promote pain. In a recent publication, our group demonstrated that 2-AG levels were elevated in patients who developed greater acute postoperative pain, suggesting that 2-AG/eicosanoid crosstalk may directly modulate acute pain in humans. However, the contribution of 2-AG metabolism toward acute pain is poorly defined and its role in eicosanoid biosynthesis and pain in humans is lacking, highlighting a major gap in our understanding of endocannabinoid metabolism and pain. The current proposal leverages rodent surgical models and patient derived samples to test the major hypothesis that MAGL activity is essential for the biosynthesis of cyclooxygenase and 5-lipoxygenase (5-LOX) derived eicosanoids, which we hypothesize operate in parallel to promote acute pain. In Aim 1, we will employ complementary pharmacological and genetic approaches to test the hypothesis that MAGL inhibition suppresses acute pain by depriving cyclooxygenase and 5-LOX enzymes of arachidonic acid for eicosanoid biosynthesis within the incision site. This aim will also employ selective inhibitors and 5-LOX KO mice to test the hypothesis that 5-LOX inhibition attenuates acute pain. Aim 2 will leverage novel conditional MAGL knockout mice to identify peripheral cell populations wherein MAGL activity contributes to postoperative eicosanoid biosynthesis and pain. Aim 3 will characterize 2-AG/eicosanoid crosstalk in perioperative human tissue and will assess the contribution of 2-AG and eicosanoid levels toward acute pain in humans. The outcome of this study will provide fundamental insights into endocannabinoid/eicosanoid crosstalk and may identify MAGL as a novel target for the treatment of acute pain, thereby providing the foundation for the rapid translation of MAGL inhibitors to patients suffering from inadequately controlled pain.

项目摘要 未能充分治疗疼痛账户数千亿美元的生产力和医疗 每年的费用。根据疾病控制中心的说法，美国每天有40多人 死于过量的处方止痛药（例如vicodin和oxycontin）。因此，紧急 需要开发新的，安全和有效的非阿片类镇痛药来治疗急性和慢性疼痛。许多 外科手术会引起严重的急性疼痛，难以治疗。经历如此重大的患者 外科手术程序也有增加随后的阿片类药物成瘾的风险。所以， 改善急性疼痛控制不仅会提高患者的预后，而且还可能导致患病率降低 随后的阿片类药物滥用。内源性大麻素2-芳基烯丙基甘油（2-AG）通过激活而产生镇痛 大麻素受体。但是，2-AG也可以通过单酰基甘油脂肪酶（MAGL）水解2Ag 为了产生可以促进疼痛的下游类花生酸的蛛网膜酸，这是下游类花生酸的前体。在最近的一个 出版物，我们的小组表明，患者的急性更高 术后疼痛，表明2-ag/eicosanoid串扰可能会直接调节人类的急性疼痛。 但是，2-AG代谢对急性疼痛的贡献很差，并且其在类eicosanoid中的作用 缺乏人类生物合成和疼痛 代谢和痛苦。当前的提案利用啮齿动物手术模型和患者衍生样品进行测试 MAGL活性对于环氧酶和5-脂氧合酶的生物合成至关重要的主要假设是必不可少的。 （5-lox）衍生的类花生酸酯，我们假设它们并行起作用以促进急性疼痛。在AIM 1中，我们将 采用互补的药理和遗传学方法来检验MAGL抑制的假设 通过剥夺花生四烯酸的环氧合酶和5-氧氧化酶来抑制急性疼痛 切口部位内的生物合成。该目标还将采用选择性抑制剂和5-lox KO小鼠来测试 假设5-lox抑制会减轻急性疼痛。 AIM 2将利用新颖的条件磁淘汰赛 小鼠鉴定麦克拉活性有助于术后类花生酸的小鼠群体 生物合成和疼痛。 AIM 3将表征围手术期人体组织中的2-AG/Eicosanoid串扰，并将 评估2-AG和类eicosanoid水平对人类急性疼痛的贡献。这项研究的结果 将提供对内源性大麻素/类eicosanoid Crosstalk的基本见解，并可以将MAGL识别为一种新颖 治疗急性疼痛的靶标，从而为MAGL抑制剂的快速翻译提供了基础 给患者无法充分控制的疼痛。