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（由适用提供）：通过对A纤维化学疗法诱导的周围神经病（CIPN）的靶向沉默来治疗化学疗法诱导的神经性疼痛，这是许多常用类抗癌剂类别的严重副作用。 CIPN可以导致降低剂量或癌症治疗中断。紫杉醇（例如紫杉醇）是人类化学疗法中最有效，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会引起疼痛的神经病。化学疗法诱导的神经性疼痛仍然没有研究和治疗。神经性疼痛是一种与周围和中枢神经系统病理变化相关的令人衰弱的综合征。对光机械刺激（机械性异常性）的高敏性是神经性疼痛的最常见和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神经损伤引起的啮齿动物中的机械性异常。相比之下，髓鞘的A纤维的选择性压缩块废除了人类触摸诱发的神经性疼痛。最近的一项研究表明，化学疗法后，NAV1.8阳性伤害感受器（C纤维）并不需要神经性疼痛的发展。总之，这些结果表明A纤维对于维持神经性疼痛至关重要，而靶向A纤维的靶向沉默可能是对化学疗法引起的神经性疼痛的有效治疗方法。良好的确立的是，C纤维可以通过TRPV1介导的膜不受欢迎的钠通道阻滞剂（QX-314）选择性阻止。但是，尚未发现特别是沉默A纤维的工具。传统上，类似Toll的接收器 （TLR）通过免疫细胞表达并参与先天免疫。然而，TLR 3和7在小背根神经（DRG）神经元中也表达，并与离子通道耦合，以使其具有疼痛和瘙痒的感觉。有趣的是，我们发现TLR5在共表达A纤维标记NF-200的大型DRG神经元中表达。该应用的中心假设是TLR5介导的A纤维通过靶向的沉默。 QX-314的摄取可以有效治疗化学疗法引起的神经性疼痛。拟议的研究将采用多学科方法，包括对诱发和持续的疼痛，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的行为测试。 A纤维的选择性沉默可以作为神经性疼痛的新型治疗方法。我们的试点研究还发现，TLR5是在人A纤维大DRG神经元中表达的。因此，拟议的研究将是开发针对CIPN患者神经性疼痛的新治疗方法的关键步骤。