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

 描述(申请人提供)：通过靶向沉默A纤维治疗化疗引起的神经病理性疼痛化疗诱导的周围神经病(CIPN)是许多常用类别抗癌药物的严重副作用。CIPN可以减少剂量或停止癌症治疗。紫杉烷，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，它们会导致大多数接受化疗的癌症患者出现痛苦的神经病变。化疗引起的神经病理性疼痛仍未得到研究和治疗。神经病理性疼痛是一种与周围和中枢神经系统的病理变化相关的衰弱综合征。对光机械刺激(机械超敏)过敏是神经病理性疼痛最常见和最令人痛苦的症状之一。研究表明，消融或沉默C纤维伤害性感受器并不能减少神经损伤引起的啮齿动物机械性痛觉异常。相比之下，有髓A纤维的选择性压迫阻断可以消除人类触觉诱发的神经病理性疼痛。最近的一项研究表明，NAV1.8阳性的伤害性感受器(C纤维)不是化疗后神经病理性疼痛发生所必需的。综上所述，这些结果表明，A纤维对维持神经病理性疼痛至关重要，靶向沉默A纤维可能是治疗化疗引起的神经病理性疼痛的有效方法。膜不通透性钠通道阻滞剂QX-314可以选择性地阻断膜不通透性钠通道阻滞剂TRPV1介导的C-纤维。然而，专门使A纤维沉默的工具尚未被发现。传统上，Toll样受体 (TLR)由免疫细胞表达，参与先天免疫。然而，TLR3和TLR7也在小的背根节(DRG)神经元中表达，并与离子通道偶联，用于痛觉和瘙痒。有趣的是，我们发现TLR5在共表达A纤维标记物NF-200的大型DRG神经元中表达。这一应用的中心假设是，通过靶向摄取QX-314，TLR5介导的A纤维沉默可以有效地治疗化疗引起的神经病理性疼痛。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、Western blotting、qPCR、转基因小鼠和电生理学。选择性沉默A纤维可能成为治疗神经病理性疼痛的一种新方法。我们的初步研究还发现，TLR5在人的A纤维大型背根节神经元中有表达。因此，这项拟议的研究将是为CIPN患者开发新的神经病理性疼痛治疗方法的关键一步。

 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.