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.

项目概要 未能充分治疗疼痛导致生产力和医疗损失数千亿美元 每年的开支。据疾病控制中心称，美国每天有超过 40 人 死于过量服用处方止痛药（例如维柯丁和奥施康定）。因此，有一个紧急的 需要开发新的、安全的、有效的非阿片类镇痛药来治疗急性和慢性疼痛。许多 外科手术会引起难以治疗的严重急性疼痛。接受此类重大手术的患者 外科手术也增加了随后发生阿片类药物成瘾的风险。所以， 改善急性疼痛控制不仅可以改善患者的治疗效果，还可以降低疼痛的患病率 随后滥用阿片类药物。内源性大麻素 2-花生四烯酰甘油 (2-AG) 通过激活产生镇痛作用 大麻素受体。然而，2-AG 也可以被单酰基甘油脂肪酶 (MAGL) 水解 生成花生四烯酸，花生四烯酸是下游类二十烷酸的前体，可促进疼痛。在最近的一次 在发表的文章中，我们的小组证明，在病情严重的患者中，2-AG 水平升高。 术后疼痛，表明 2-AG/类二十烷酸串扰可能直接调节人类的急性疼痛。 然而，2-AG 代谢对急性疼痛的贡献尚不清楚，其在类二十烷酸中的作用 人类缺乏生物合成和疼痛，凸显了我们对内源性大麻素的理解存在重大差距 新陈代谢和疼痛。目前的提案利用啮齿动物手术模型和患者来源的样本进行测试 主要假设是 MAGL 活性对于环氧合酶和 5-脂氧合酶的生物合成至关重要 (5-LOX) 衍生的类二十烷酸，我们假设它们同时起作用以促进急性疼痛。在目标 1 中，我们将 采用互补的药理学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-LOX 酶来产生类二十烷酸，从而抑制急性疼痛 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 抑制可减轻急性疼痛。目标 2 将利用新颖的条件 MAGL 淘汰赛 小鼠鉴定外周细胞群，其中 MAGL 活性有助于术后类二十烷酸 生物合成和疼痛。目标 3 将表征围手术期人体组织中的 2-AG/类二十烷酸串扰，并将 评估 2-AG 和类二十烷酸水平对人类急性疼痛的影响。这项研究的结果 将为内源性大麻素/类二十烷酸串扰提供基本见解，并可能将 MAGL 视为一种新颖的 治疗急性疼痛的靶点，从而为MAGL抑制剂的快速转化提供基础 对于疼痛控制不当的患者。