MECHANISMS OF ANTI-NOCICEPTIVE EFFECT OF PROSTAGLANDIN METABOLITE

描述（由申请人提供）：摘要在人类中，机械性超敏反应的特征在于对简单运动的敏感性，并被描述为刺痛和刺痛;它是许多炎性和神经性疼痛病症的标志。前列腺素D2的代谢产物15-脱氧-12，14-前列腺素J2（15 d-PGJ 2）最好的特征是作为一种抗炎前列腺素。最近，我们发现15 d-PGJ 2激活热TRP离子通道TRPA 1在异源表达系统和背根神经节（DRG）神经元，诱导伤害性行为在小鼠中通过TRPA 1依赖的机制。在这里，我们报告15 d-PGJ 2也是外周作用的抗伤害感受化合物，在几种疼痛模型中减弱对机械刺激的超敏反应。我们推测15 d-PGJ 2减弱机械超敏性的机制是通过TRPA 1通道的初始激活，然后脱敏。我们将利用行为、分子和电生理学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，我们将探索15 d-PGJ 2作为外周作用疼痛治疗剂的疗效。 公共卫生相关性：瞬时受体电位离子通道TRPA 1是一种提出的冷门控和机械门控通道，也被各种刺激物、炎症介质和细胞应激产物激活。动物研究表明，TRPA 1在急性疼痛信号传导以及炎症和神经性损伤诱导的超敏反应中起作用。在这个提议中，我们已经确定了一种内源性抗炎化合物，可以降低几种疼痛模型中的机械超敏反应，我们提出了TRPA 1依赖性机制。我们将通过完成一组行为测试和细胞研究来证明这种化合物的镇痛作用和特异性。我们的研究将有助于TRPA 1靶向疼痛治疗的未来发展。

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.