Peripheral Mechanisms of Kappa Opioid Receptor-Mediated Cold Hypersensitivity

项目摘要 本研究的总体目标是更好地了解kappa阿片受体（KOR）系统如何 调节冷过敏，最终目的是发现一个新的治疗靶点。冷痛影响 许多不同的患者群体，大部分都没有得到治疗。神经性疼痛伴冷异常性疼痛是 估计影响15%至50%的神经性疼痛患者。对许多患者来说，冷痛往往是一种副作用 会变成一种慢性的衰弱状态接受含铂药物化疗的患者 报告对冷刺激的敏感性和疼痛增加。此外，对冷的高度敏感性在以下方面是有问题的： 那些被诊断为多发性硬化症的人对于其他人来说，冷痛是更大更复杂的疼痛状况的一部分。的 最常报道的用于治疗神经性疼痛的药物是非甾体抗炎药 （非甾体抗炎药），阿片类药物和抗癫痫药，不缓解或治疗冷敏感性增加，主要是因为 我们对冷痛的调节机制还没有清楚的认识。本研究 重点是更好地理解外周KORs调节冷过敏的机制， 冷痛。本提案的第一个目标是使用转基因和药理学相结合的方法来评估 外周KOR表达在冷过敏和冷痛调节中的必要性。第二 目的是确定背根神经节中KORs调节TRPA1信号的机制， 并确定TRPA 1通道参与KOR介导的冷过敏的必要性。 第三个目的是测试背根神经节中的KORs是否也调节TRPM8信号传导。在最后的目标中， 将使用来自器官捐赠者的人背根神经节组织来确定KOR对TRP功能的调节是否 存在于人类中。总之，这些方法将使我们能够剖析外周κ阿片类物质在寒冷中的作用。 过敏和冷痛。了解KOR系统调节冷的机制 超敏反应以及该系统如何参与冷痛的调节将具有重要意义 不仅有助于我们理解冷过敏的基本机制， 治疗目标，使我们能够治疗冷过敏和疼痛。

Project Summary The overall goal of this research is to better understand the how the kappa opioid receptor (KOR) system modulates cold hypersensitivity with the ultimate goal of uncovering a novel therapeutic target. Cold pain affects a number of diverse groups of patients and goes largely untreated. Neuropathic pain with cold allodynia is estimated to affect 15% to 50% of neuropathic pain patients. For many patients, cold pain is often a side effect that becomes a chronic debilitating condition. Patients undergoing chemotherapy using platinum-based drugs report increased sensitivity and pain to cold stimuli. Furthermore, heightened sensitivity to cold is problematic in those diagnosed with multiple sclerosis. For others, cold pain is part of larger more complex pain condition. The most commonly reported medications used to treat neuropathic pain are non-steroidal anti-inflammatory drugs (NSAIDs), opioids and anti-epileptics, which do not relieve or treat heightened cold sensitivity, primarily because we do not have clear understanding of the mechanisms involved in the modulation of cold pain. This research focuses on better understanding the mechanism by which peripheral KORs modulate cold hypersensitivity and cold pain. The first aim of this proposal will use combined transgenic and pharmacological approaches to assess the necessity of peripheral KOR expression in the modulation of cold hypersensitivity and cold pain. The second aim will determine the mechanism by which KORs in dorsal root ganglion can modulate TRPA1 signaling, as well as determine the necessity of the involvement of TRPA1 channels in KOR mediated cold hypersensitivity. The third aim will test whether KORs in dorsal root ganglion also modulate TRPM8 signaling. In the final aim, will use human dorsal root ganglion tissue from organ donors to determine if the KOR-modulation of TRP function exists in humans. Together, these approaches will allow us to dissect the role of peripheral kappa opioids in cold hypersensitivity and cold pain. Understanding the mechanisms by which the KOR system modulates cold hypersensitivity and how this system may also be involved in modulation of cold pain will have major implications not only in our understanding of basic mechanisms of cold hypersensitivity, but may also open up alternative therapeutic targets to allow us to treat cold hypersensitivity and pain.