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

点击翻译按钮获取中文摘要

 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.