Role of Epoxygenated Fatty Acids in Modulating Pain

环氧化脂肪酸在调节疼痛中的作用

• 批准号: 8446055
• 负责人: BRUCE D HAMMOCK
• 金额: $ 19.64万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8446055
• 关键词: Acids; Address; Adverse effects; Analgesics; Anti Inflammatory Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Arachidonic Acids; Attenuated; Award; Axon; Behavior; Behavioral; Behavioral Assay; Biochemical; Biological; Brain region; Carrageenan; Characteristics; Cyclic AMP; Cytochrome P450; Dendrites; Development; Diagnostic; Disease; Epoxide hydrolase; Fatty Acids; Functional disorder; Gene Expression Profiling; Health; Immunohistochemistry; Inflammation; Inflammatory; Investigation; Knowledge; Lead; Left; Lipids; Lipoxygenase; Lumbar spinal cord structure; Maintenance; Measures; Mediating; Microsomal Epoxide Hydrolase; Modeling; Monitor; Motor; Nature; Neuraxis; Neuroglia; Neurons; Nociception; Outcome; Pain; Pain management; Pathway interactions; Peripheral; Pharmaceutical Preparations; Phosphodiesterase Inhibitors; Physicians; Physiological; Plasma; Play; Positioning Attribute; Postoperative Pain; Prostaglandin-Endoperoxide Synthase; Rattus; Research Personnel; Resistance; Role; Route; Skin; Spinal; Surgical incisions; System; Testing; Therapeutic; Time; Tissues; analog; chronic pain; clinically relevant; inflammatory marker; inflammatory neuropathic pain; inflammatory pain; inhibitor/antagonist; insight; liquid chromatography mass spectrometry; metabolomics; nervous system disorder; novel; painful neuropathy; phosphoric diester hydrolase; presynaptic; public health relevance; rapid technique; research study; response

DESCRIPTION (provided by applicant): Great demand for novel pain therapies exists for chronic pain states. The arachidonic acid (ARA) cascade is a pivotal inflammatory pain pathway, and many studies addressed the cyclooxygenase (cox) and lipoxygenase (lox) branches of this cascade. However, the emerging importance of a third branch, the cytochrome P450 pathway, offers novel alternatives for pain modulation. In contrast to the inflammatory cox and lox metabolites, the cytochrome P450-generated ARA metabolites, epoxyeicosatrienoic acids (EETs), are potent physiological anti-inflammatory/antihyperalgesic molecules. These bioactive lipids have very short half lives and inhibiting their degradation mediated by soluble epoxide hydrolase (sEH, EC 3.3.2.3) leads to antinociception. Inhibitors of sEH are effective in models of inflammatory and neuropathic pain, but it is unclear how sEH inhibition attenuates pain, warranting further investigation of this novel pathway. The sEH is well expressed in the peripheral and central nervous system, in the neurons and the glial cells, with spatial selectivity of expression among brain regions. Inhibitors of sEH (sEHIs) block nocifensive behavior, while leaving intact normal nociceptive and motor function. Thus in this study we will test the hypothesis that epoxygenated fatty acids and sEHI have a modulatory role in pain pathophysiology. To address this hypothesis, the levels of the EpFAs and their degradation products in the skin and the lumbar spinal cord in two distinct models of pain will be monitored. Levels of EpFAs will then be modulated in two distinct models of pain by different approaches; a) by exogenous EpFAs, b) by inhibiting the sEH, c)by inhibiting phosphodiesterases and d) by novel synthetic analogues of EpFAs that are resistant to sEH mediated degradation. We will utilize the carrageenan induced inflammatory pain model to identify anti- hyperalgesic EpFAs. The bioactivity of anti-nociceptive EpFAs will be validated in a clinically relevant model, the incisional pain model. We will use a combination of behavioral assays, biochemical and metabolomic analysis to understand the interactions of EpFAs with nociceptive pathways. We will produce a characteristic/diagnostic LC/MS/MS generated metabolomic profile of the intraplantar carrageenan and the plantar incisional pain models in rats. The incisional pain in particular is less well studied in regard to alterations in bioactive lipid metabolites. The target metabolites (80+ bioactive lipids) are from all three branches of the AA cascade including major cox, lox, cytochrome P450 and the sEH products including lipid metabolites of EPA and DHA, allowing us to investigate metabolite flux and crosstalk between biological cascades. The proposed studies will result in an advanced understanding of the antinociceptive mechanism of action of EpFAs and sEH inhibitors, and provide novel insights to the underlying mechanisms of lipidomic and biochemical alterations in response to pain. The knowledge generated by these experiments is likely to lead to the development of novel classes of agents that target pathways that have not been recognized previously.

描述（由申请人提供）：慢性疼痛状态对新型疼痛疗法存在巨大需求。花生四烯酸 (ARA) 级联是关键的炎症疼痛途径，许多研究涉及该级联的环氧合酶 (cox) 和脂氧合酶 (lox) 分支。然而，第三个分支（细胞色素 P450 通路）的重要性日益显现，为疼痛调节提供了新的替代方案。与炎症性 cox 和 lox 代谢物相反，细胞色素 P450 生成的 ARA 代谢物环氧二十碳三烯酸 (EET) 是有效的生理抗炎/抗痛觉过敏分子。这些生物活性脂质的半衰期非常短，抑制可溶性环氧化物水解酶（sEH，EC 3.3.2.3）介导的降解可产生镇痛作用。 sEH 抑制剂对炎症和神经性疼痛模型有效，但尚不清楚 sEH 抑制如何减轻疼痛，需要对这一新途径进行进一步研究。 sEH 在周围和中枢神经系统、神经元和神经胶质细胞中良好表达，具有空间选择性 大脑区域之间的表达。 sEH (sEHIs) 抑制剂可阻止伤害行为，同时保留正常的伤害感受和运动功能。因此，在本研究中，我们将检验环氧化脂肪酸和 sEHI 在疼痛病理生理学中具有调节作用的假设。为了验证这一假设，将监测两种不同疼痛模型中皮肤和腰脊髓中 EpFA 及其降解产物的水平。然后，通过不同的方法在两种不同的疼痛模型中调节 EpFA 的水平； a) 通过外源 EpFA，b) 通过抑制 sEH，c) 通过抑制磷酸二酯酶，以及 d) 通过可抵抗 sEH 介导的降解的新型 EpFA 合成类似物。我们将利用角叉菜胶诱导的炎症疼痛模型来鉴定抗痛觉过敏 EpFA。抗伤害性 EpFA 的生物活性将在临床相关模型（切口痛模型）中得到验证。我们将结合行为分析、生化和代谢组学分析来了解 EpFA 与伤害感受途径的相互作用。我们将产生大鼠足底内角叉菜胶和足底切口疼痛模型的特征/诊断性 LC/MS/MS 生成的代谢组学特征。关于生物活性脂质代谢物的变化，尤其是切口痛的研究还较少。目标 代谢物（80 多种生物活性脂质）来自 AA 级联的所有三个分支，包括主要 cox、lox、细胞色素 P450 和 sEH 产品，包括 EPA 和 DHA 的脂质代谢物，使我们能够研究代谢物通量和生物级联之间的串扰。拟议的研究将加深对 EpFA 和 sEH 抑制剂的抗伤害作用机制的了解，并为响应疼痛的脂质组学和生化改变的潜在机制提供新的见解。这些实验产生的知识可能会导致针对以前未被识别的途径的新型药物的开发。