MECHANISMS OF ANTI-NOCICEPTIVE EFFECT OF PROSTAGLANDIN METABOLITE

前列腺素代谢物的抗伤害作用机制

基本信息

批准号：
7920110
负责人：
GINA M STORY
金额：
$ 19万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7920110
关键词：
9-deoxy-delta-9-prostaglandin D2 Ache Acute Acute Pain Adverse effects Agonist Analgesics Animals Anti-Inflammatory Agents Anti-inflammatory Applications Grants Attenuated Behavior Behavioral Bradykinin Calcium Cellular Stress Chronic Cysteine Development Dinoprostone Dose Epoprostenol Foundations Freund&apos s Adjuvant Future Human Hyperalgesia Hypersensitivity Image Inflammation Inflammation Mediators Inflammatory Injection of therapeutic agent Injury Investigation Ion Channel Irritants Knockout Mice Knowledge Maintenance Mechanical Stimulation Mechanics Mediating Modeling Molecular Morphine Movement Mus Mutate Neurons Neuropathy Nociception Nociceptors Oxidative Stress Pain Peripheral Pharmaceutical Preparations Play Posterior Horn Cells Prostaglandin D2 Prostaglandins Relative (related person)Reporting Role Route Signal Transduction Specificity Spinal Ganglia Stimulus System TRPA1 Channel Testing Therapeutic Thermal Hyperalgesias Touch sensation Work abstracting attenuation behavior test desensitization inflammatory neuropathic pain inhibitor/antagonist mustard oil nerve injury neuromechanism public health relevance receptor research study small molecule tool

项目摘要

DESCRIPTION (provided by applicant): Abstract In humans, mechanical hypersensitivity is characterized by sensitivity to simple movements and is described as shooting and stabbing pain; it is a hallmark of many inflammatory and neuropathic pain conditions. The prostaglandin D2 metabolite, 15-deoxy- 12,14-prostaglandin J2 (15d-PGJ2), is best characterized as an anti-inflammatory prostaglandin. Recently we showed 15d-PGJ2 activates thermoTRP ion channel TRPA1 in heterologous expression systems and in dorsal root ganglion (DRG) neurons, inducing nociceptive behavior in mice via a TRPA1-dependent mechanism. Here we report that 15d-PGJ2 is also a peripherally acting anti- nociceptive compound, attenuating hypersensitivity to mechanical stimuli in several pain models. We hypothesize that the mechanism of 15d-PGJ2 attenuation of mechanical hypersensitivity is via initial activation followed by desensitization of TRPA1 channels. We will test this hypothesis by utilizing behavioral, molecular and electrophysiological tools. Our studies lay the foundation for future work in which we will explore the efficacy of 15d-PGJ2 as a peripherally acting pain therapeutic. PUBLIC HEALTH RELEVANCE: The Transient Receptor Potential ion channel TRPA1 is a proposed cold- and mechanically-gated channel that is also activated by a variety of irritants, inflammatory mediators and products of cellular stress. Animal studies demonstrate that TRPA1 plays a role in acute pain signaling as well as inflammation- and neuropathic injury- induced hypersensitivity. In this proposal we have identified an endogenous anti-inflammatory compound that reduces mechanical hypersensitivity in several pain models and we propose a TRPA1-dependent mechanism. We will demonstrate the analgesic action and specificity of this compound by completing a panel of behavioral tests and cellular studies. Our studies will contribute to the future development of TRPA1-targeted pain therapeutics.

描述（由申请人提供）：在人类中的摘要中，机械性超敏反应的特征是对简单运动的敏感性，被描述为射击和刺痛。它是许多炎症和神经性疼痛状况的标志。前列腺素D2代谢产物，15-脱氧-12,14-促生蛋白J2（15d-PGJ2），最好以抗炎前列腺素为特征。最近，我们显示15d-PGJ2在异源表达系统和背根神经节（DRG）神经元中激活ThermoTRP离子通道TRPA1，通过TRPA1依赖性机制在小鼠中诱导了伤害性行为。在这里，我们报告说，15d-PGJ2也是一种外围作用的抗伤害性化合物，在几种疼痛模型中降低了对机械刺激的超敏反应。我们假设机械性超敏反应的15d-PGJ2衰减的机制是通过初始激活，然后是TRPA1通道的脱敏。我们将利用行为，分子和电生理工具来检验这一假设。我们的研究为未来的工作奠定了基础，我们将探讨15d-PGJ2作为外周作用疼痛治疗的功效。公共卫生相关性：瞬态受体电位离子通道TRPA1是一种提出的冷和机械门控通道，也被各种刺激性，炎症介质和细胞应激的产物激活。动物研究表明，TRPA1在急性疼痛信号传导以及炎症和神经性损伤引起的超敏反应中起作用。在此提案中，我们已经确定了一种内源性抗炎化合物，该化合物在几种疼痛模型中降低了机械性超敏反应，我们提出了一种依赖TRPA1的机制。我们将通过完成一系列行为测试和细胞研究来证明该化合物的镇痛作用和特异性。我们的研究将有助于TRPA1靶向疼痛疗法的未来发展。