Treating chemotherapy-induced neuropathic pain by targeted silencing of A-fibers

通过靶向沉默 A 纤维治疗化疗引起的神经性疼痛

• 批准号: 9000187
• 负责人: RU-RONG JI
• 金额: $ 23.85万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9000187
• 关键词: Ablation; Address; Adverse effects; Agonist; Amyloid beta-Protein; Antineoplastic Agents; Axon; Biological Assay; C Fiber; Cancer Patient; Cells; Chemotherapy-induced peripheral neuropathy; Coupled; Development; Distress; Dose; Dose-Limiting; Drug usage; Electrophysiology (science); Esthesia; Fiber; Human; Hypersensitivity; Immune; Immunohistochemistry; In Situ Hybridization; Injection of therapeutic agent; Ion Channel; Knockout Mice; Lead; Light; Mechanics; Mediating; Membrane; Modeling; Mus; Natural Immunity; Neuraxis; Neurons; Nociceptors; Paclitaxel; Pain; Patients; Peripheral; Pilot Projects; Regulation; Rodent; Skin; Sodium; Sodium Channel; Sodium Channel Blockers; Spinal Cord; Spinal Ganglia; Stimulus; Symptoms; Syndrome; TLR3 gene; TLR5 gene; TRPV1 gene; Testing; Toll-like receptors; Touch sensation; Toxic effect; Transgenic Mice; Western Blotting; allodynia; behavior test; cancer therapy; chemotherapy; effective therapy; in vivo; interdisciplinary approach; mechanical allodynia; nerve injury; novel; novel therapeutics; painful neuropathy; patch clamp; public health relevance; response; sciatic nerve; taxane; tool; uptake

 DESCRIPTION (provided by applicant): Treating chemotherapy-induced neuropathic pain by targeted silencing of A-fibers Chemotherapy-induced peripheral neuropathy (CIPN) is a serious side effect of many commonly used classes of anti-cancer agents. CIPN can lead to dose reductions or discontinuation of cancer therapy. Taxanes, such as paclitaxel, are among the most effective and extensively used drugs in human chemotherapy. Unfortunately, they cause painful neuropathy in most cancer patients receiving chemotherapy. Chemotherapy-induced neuropathic pain remains under-studied and under-treated. Neuropathic pain is a debilitating syndrome associated with pathological changes in the peripheral and central nervous system. Hypersensitivity to light mechanical stimuli (mechanical allodynia) is one of the most common and distressing symptoms of neuropathic pain. Studies have shown that ablation or silencing of C- fibers nociceptors does not reduce nerve injury-induced mechanical allodynia in rodents. In contrast, selective compression block of myelinated A-fibers abolishes touch-evoked neuropathic pain in humans. A recent study demonstrates that Nav1.8-positive nociceptors (C-fibers) are not required for the development of neuropathic pain following chemotherapy. Together, these results indicate that A-fibers are critical for maintaining neuropathic pain, and that targeted silencing of A-fibers could be an effective treatment for neuropathic pain induced by chemotherapy. It is well-established that C-fibers can be selectively blocked by TRPV1-mediated entry of membrane- impermeable sodium channel blocker, QX-314. However, tools that specifically silence A-fibers have not yet been discovered. Traditionally, toll-like receptors (TLR) are expressed by immune cells and participate in innate immunity. However, TLR 3 &7 are also expressed in small dorsal root ganglia (DRG) neurons, and are coupled to ion channels, for the sensations of pain and itch. Interestingly, we found that TLR5 was expressed in large DRG neurons co-expressing the A-fiber marker NF-200. The central hypothesis of this application is that TLR5-mediated silencing of A-fibers, via targeted uptake of QX-314, can effectively treat neuropathic pain induced by chemotherapy. The proposed studies will use a multidisciplinary approach, including behavior testing of evoked and ongoing pain, immunohistochemistry, in situ hybridization, western blotting, qPCR, transgenic mice, and electrophysiology. Selective silencing of A-fibers may serve as a novel treatment for neuropathic pain. Our pilot studies also found that TLR5 was expressed in human A-fiber large DRG neurons. Therefore, the proposed study will be a critical step toward developing new treatments for neuropathic pain in patients with CIPN.

 描述（由申请人提供）：通过靶向沉默A-纤维治疗化疗诱导的神经性疼痛化疗诱导的周围神经病变（CIPN）是许多常用类别的抗癌剂的严重副作用。CIPN可导致剂量减少或癌症治疗中止。紫杉烷类，如紫杉醇，是人类化疗中最有效和最广泛使用的药物之一。不幸的是，它们在大多数接受化疗的癌症患者中引起疼痛的神经病变。化疗引起的神经性疼痛仍然研究不足，治疗不足。神经性疼痛是一种与外周和中枢神经系统病理变化相关的衰弱综合征。对光机械刺激的超敏反应（机械性异常性疼痛）是神经性疼痛最常见和最令人痛苦的症状之一。研究表明，C纤维伤害感受器的消融或沉默不会减少啮齿动物中神经损伤诱导的机械异常性疼痛。相比之下，有髓A纤维的选择性压迫阻断消除了人类的触摸诱发的神经性疼痛。最近的一项研究表明，Nav1.8阳性伤害感受器（C纤维）不是化疗后神经性疼痛发展所必需的。总之，这些结果表明，A-纤维对于维持神经性疼痛至关重要，并且A-纤维的靶向沉默可能是化疗诱导的神经性疼痛的有效治疗。已经确定的是，C-纤维可以通过TRPV 1介导的膜不可渗透钠通道阻断剂QX-314的进入而选择性地阻断。然而，专门沉默A纤维的工具尚未被发现。传统上，Toll样受体 (TLR)由免疫细胞表达并参与先天免疫。然而，TLR 3和7也在小背根神经节（DRG）神经元中表达，并且与离子通道偶联，用于疼痛和瘙痒的感觉。有趣的是，我们发现TLR 5在共表达A纤维标记物NF-200的大DRG神经元中表达。本申请的中心假设是，通过靶向摄取QX-314，TLR 5介导的A-纤维沉默可以有效治疗化疗诱导的神经性疼痛。拟议的研究将使用多学科方法，包括诱发和持续疼痛的行为测试、免疫组织化学、原位杂交、蛋白质印迹、qPCR、转基因小鼠和电生理学。选择性沉默A-纤维可能作为一种新的治疗神经性疼痛。我们的初步研究还发现TLR 5在人A纤维大DRG神经元中表达。因此，这项研究将是开发CIPN患者神经性疼痛新疗法的关键一步。