Inhibiting peripheral diacylglycerol lipase beta - a novel target for pain relief

抑制外周二酰甘油脂肪酶β——缓解疼痛的新靶点

• 批准号: 9222649
• 负责人: Jenny Wilkerson
• 金额: $ 4.43万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-03-10 至 2017-11-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9222649
• 关键词: 2-arachidonylglycerol; ABHD6 gene; Acute; Adverse effects; Anabolism; Analgesics; Ants; Arachidonic Acids; Behavior; Behavioral; Biological Assay; Biological Markers; Blood; Brain; CCL2 gene; Clinical Pharmacology; Contralateral; Data; Depressed mood; Dinoprostone; Dose; Eicosanoid Production; Eicosanoids; Endocannabinoids; Environment; Enzymes; Foundations; Genetic; Immune; Immune system; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Injectable; Interleukin-1; Interleukin-10; Knowledge; Ligands; Link; Lipopolysaccharides; Maintenance; Mediating; Mediator of activation protein; Modeling; Mus; Nervous system structure; Neurons; Pain; Pain management; Pathway interactions; Peripheral; Peritoneal Macrophages; Pharmaceutical Preparations; Pharmacology; Play; Principal Investigator; Production; Property; Prostaglandins; Public Health; Regulation; Research; Research Personnel; Research Proposals; Role; Site; Societies; Spinal; Spinal Cord; Subarachnoid Space; Synaptic plasticity; TNF gene; Testing; Therapeutic; Thermal Hyperalgesias; Time; Tissue Sample; Tissues; Training; Valdecoxib; Work; allodynia; anandamide; assay development; career; chronic pain; cytokine; endogenous cannabinoid system; genetic approach; in vivo; inflammatory modulation; inflammatory pain; inhibitor/antagonist; insight; intraperitoneal; lipoprotein lipase; mechanical allodynia; medical attention; novel; pain behavior; preference; public health relevance; response; skills; ventricular system

DESCRIPTION (provided by applicant): The Identification of novel pharmacological approaches to reduce pain is critical from public health perspective. One of the most common reasons to seek medical attention is that of pain, and collectively pain represents a huge financial burden to society. Once thought to be only mediated solely by neuronal firing, the immune system has been revealed to play a critical role in the regulation, maintenance and transition from acute to chronic pain states. One class that has broad immune relevance during periods of pain is the prostaglandins. Recent discoveries yield insight on a novel pathway of diacylglycerol lipase (DAGL) involvement in the ultimate formation of arachidonic acid, which can then be transformed into prostaglandins. In vitro work shows that inhibiting DAGL-�, one form of DAGL, reduces the biosynthesis of 2-arachidonyl glycerol, the endocannabinoid ligand and a precursor of arachidonic acid. This reduction in free arachidonic acid in turn, results in decreases in the formation of the prostaglandin PGE2 and the pro-inflammatory cytokine tumor necrosis factor- alpha (TNF-�). Therefore, we hypothesize that pharmacological inhibition of DAGL-� with a novel compound, KT109, in mice will lower pro-inflammatory cytokines, prostaglandins and other inflammatory mediators of pain, leading to reversal of behaviors associated with pain. Accordingly, the objectives of this training plan are to characterize the ant-pain effects of DAGL-� inhibitors in murine pain models and determine the underlying in vivo mechanism(s) of action of this class of compounds. The proposed aims to examine these objectives are: 1.) Aim 1: Elucidate the consequences of blocking DAGL- � in inflammatory pain assays. 2.) Determine the locus of action mediating the pain stimulated and pain depressed behavioral effects of DAGL-� inhibitors in the LPS model of inflammatory pain. 3.) Determine the effects of DAGL-� inhibition on pro-inflammatory and pain mediators. Under these aims the consequences of inhibiting DAGL-� will be investigated in the LPS inflammatory pain model, and the importance of prostaglandins and other pro-inflammatory mediators will be identified. This work aiming to identify a novel mechanism of prostaglandin regulation and subsequent pain control will provide a critical training plan for Dr. Wilkerson to gain the necessary bench skills and conceptual framework to become an independent investigator in developing analgesics that lack abuse potential. Ultimately, the knowledge obtained from this research has the potential to establish DAGL-� as a target linking upstream prostaglandin control to pain relief.

描述（由申请方提供）：从公共卫生的角度来看，确定减轻疼痛的新型药理学方法至关重要。寻求医疗照顾的最常见原因之一是疼痛，而疼痛对社会来说是一个巨大的经济负担。免疫系统曾经被认为仅由神经元放电介导，但现已发现免疫系统在急性疼痛状态向慢性疼痛状态的调节、维持和过渡中起着关键作用。在疼痛期间具有广泛免疫相关性的一类是三兰素。最近的发现揭示了二酰基甘油脂酶（DAGL）参与花生四烯酸最终形成的新途径，然后花生四烯酸可以转化为前列腺素。体外研究表明，抑制DAGL-β（DAGL的一种形式）会减少2-花生四烯酸甘油（内源性大麻素配体和花生四烯酸前体）的生物合成。这种游离花生四烯酸的减少反过来又导致前列腺素PGE 2和促炎细胞因子肿瘤坏死因子-α（TNF-α）的形成减少。因此，我们假设，在小鼠中用一种新的化合物KT 109对DAGL-β进行药理学抑制，将降低促炎细胞因子、阿邦定和其他疼痛炎症介质，从而逆转与疼痛相关的行为。因此，本培训计划的目的是表征DAGL-β抑制剂在小鼠疼痛模型中的抗疼痛作用，并确定这类化合物的潜在体内作用机制。审查这些目标的拟议目标是：1。）目的1：阐明在炎性疼痛试验中阻断DAGL-β的后果。2.）的情况。确定DAGL-β抑制剂在炎症性疼痛的LPS模型中介导疼痛刺激和疼痛抑制行为效应的作用位点。3.）第三章确定DAGL-β抑制对促炎和疼痛介质的影响。在这些目标下，将在LPS炎性疼痛模型中研究抑制DAGL-β的后果，并将确定野牡丹素和其他促炎介质的重要性。这项旨在确定前列腺素调节和随后疼痛控制的新机制的工作将为Wilkerson博士提供关键的培训计划，以获得必要的实验室技能和概念框架，成为开发缺乏滥用潜力的镇痛药的独立研究者。最终，从这项研究中获得的知识有可能建立DAGL-β作为连接上游前列腺素控制和疼痛缓解的靶点。