Peripheral Mechanisms of Kappa Opioid Receptor-Mediated Cold Hypersensitivity

Kappa阿片受体介导的冷过敏的外周机制

• 批准号: 10454041
• 负责人: Ream Al-Hasani
• 金额: $ 44.16万
• 依托单位: ST. LOUIS COLLEGE OF PHARMACY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454041
• 关键词: ANK1 gene; Affect; Afferent Neurons; Animals; Antiepileptic Agents; Automobile Driving; Bathing; Behavioral; Binding; Biological Assay; Calcium; Calcium Signaling; Cells; Chemotherapy-induced peripheral neuropathy; Chronic; Complex; Data; Detection; Diagnosis; Electrophysiology (science); Esthesia; Etiology; Future; GTP-Binding Proteins; Goals; Human; Hypersensitivity; Image; In Situ Hybridization; Knock-out; Knockout Mice; Measures; Mechanics; Mediating; Modeling; Multiple Sclerosis; Mus; Neuraxis; Neurons; Neuropathy; Non-Steroidal Anti-Inflammatory Agents; Nucleus Accumbens; Opioid; Opioid Antagonist; Opioid agonist; Organ Donor; Pain; Pathologic; Patients; Peripheral; Peripheral Nervous System; Pertussis Toxin; Pharmaceutical Preparations; Pharmacology; Platinum; Play; Receptor Activation; Reporting; Research; Rodent Model; Role; Signal Transduction; Spinal Ganglia; Stimulus; Syndrome; System; TRP channel; TRPA channel; Tail; Temperature; Testing; Tissues; Transgenic Organisms; Wild Type Mouse; Withdrawal; allodynia; base; chemotherapy; chronic constriction injury; chronic pain; effective therapy; human tissue; in vivo; kappa opioid receptors; negative affect; new therapeutic target; pain patient; painful neuropathy; preservation; receptor; receptor expression; recruit; side effect; therapeutic target; viral rescue

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.

项目概要 这项研究的总体目标是更好地了解 kappa 阿片受体 (KOR) 系统如何 调节冷超敏反应，最终目标是发现新的治疗靶点。冷痛影响 许多不同的患者群体，并且基本上没有得到治疗。伴有冷异常性疼痛的神经性疼痛是 据估计影响 15% 至 50% 的神经性疼痛患者。对于许多患者来说，冷痛往往是一种副作用 这会成为一种慢性的使人衰弱的疾病。接受铂类药物化疗的患者 报告对冷刺激的敏感性和疼痛增加。此外，对寒冷的敏感性增加也是一个问题 被诊断患有多发性硬化症的人。对于其他人来说，冷痛是更大更复杂的疼痛状况的一部分。这 最常报告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，它们不能缓解或治疗高度的寒冷敏感性，主要是因为 我们对调节冷痛的机制还没有清楚的了解。这项研究 重点是更好地了解外周 KOR 调节冷过敏的机制 冷痛。该提案的第一个目标将使用转基因和药理学相结合的方法来评估 外周 KOR 表达在调节冷过敏和冷痛中的必要性。第二个 目标将确定背根神经节中的 KOR 调节 TRPA1 信号传导的机制，如 以及确定 TRPA1 通道参与 KOR 介导的冷超敏反应的必要性。 第三个目标是测试背根神经节中的 KOR 是否也调节 TRPM8 信号传导。在最终目标中， 将使用来自器官捐献者的人背根神经节组织来确定 TRP 功能的 KOR 调节是否 存在于人类之中。总之，这些方法将使我们能够剖析外周卡帕阿片类药物在感冒中的作用 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调节冷痛将产生重大影响 不仅有助于我们了解冷过敏的基本机制，而且还可能开辟替代方案 治疗目标使我们能够治疗冷过敏和疼痛。