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 未能充分治疗疼痛造成了数千亿美元的生产力和医疗损失 每年的开支。根据疾病控制中心的数据，在美国，每天有超过40人 死于过量的处方止痛药(如维柯丁和奥施康定)。因此，有一个紧急的 需要开发新的、安全的和有效的非阿片类止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。接受如此重大手术的患者 外科手术也增加了随后发展成阿片成瘾的风险。因此， 改善急性疼痛控制不仅将改善患者的预后，还可能导致降低 随后的阿片类药物滥用。内源性大麻素2-花生四烯基甘油(2-AG)通过激活 大麻素受体。然而，2-AG也可以被单酰基甘油脂肪酶(MAGL)水解。 以产生花生四烯酸，花生四烯酸是下游二十烷类化合物的前体，可以促进疼痛。在最近一次 发表，我们的小组证明了2-AG水平在发展为更严重急性白血病的患者中升高。 术后疼痛，提示2-AG/二十烷醇串扰可能直接调节人类的急性疼痛。 然而，2-AG代谢在急性疼痛中的作用及其在二十烷类化合物中的作用尚不清楚。 人类缺乏生物合成和疼痛，突显出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。目前的方案利用啮齿动物手术模型和患者来源的样本来测试 MAGL活性对环氧合酶和5-脂氧合酶的生物合成至关重要的主要假说 (5-LOX)衍生的二十烷基类化合物，我们假设它们是平行作用的，以促进急性疼痛。在目标1中，我们将 使用互补的药理学和遗传学方法来检验MAGL抑制的假设 通过剥夺环氧合酶和5-LOX酶的花生四烯酸来抑制二十烷类化合物的急性疼痛 在切口处的生物合成。该目标还将使用选择性抑制剂和5-LOX KO小鼠来测试 假设5-LOX抑制可以缓解急性疼痛。AIM 2将利用新的条件MAGL淘汰赛 小鼠识别MAGL活性对术后二十烷类化合物有贡献的外周细胞群 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/二十烷醇串扰，并将 评估2-AG和二十烷类激素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/二十烷类串扰的基本见解，并可能将MAGL确定为一种新的 作为治疗急性疼痛的靶点，从而为MAGL抑制剂的快速转化提供了基础 对于疼痛控制不充分的患者。