Remark bundle structure and function in neuropathic pain

备注神经病理性疼痛中束的结构和功能

• 批准号: 7212465
• 负责人: JOHN W GRIFFIN
• 金额: $ 31.48万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-05 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7212465
• 关键词: Acute; Address; Adult; Automobile Driving; Axon; Back; Behavior; Behavioral; C Fiber; CALCA gene; Calcitonin Gene-Related Peptide; Caliber; Capsaicin; Causalgia; Cutaneous; Data; Denervation; Development; Diabetes Mellitus; Dorsal; Dose; Electrophysiology (science); Environmental Wind; Exhibits; Fiber; Formalin; Freund' s Adjuvant; GDNF gene; Generations; Genetically Engineered Mouse; Growth Factor; Heating; Hyperalgesia; Injury; Knock-in Mouse; Lateral; Lead; Left; Ligation; Limb structure; Measures; Mechanics; Modeling; Mus; Mutation; Nerve; Nerve Degeneration; Nerve Fibers; Nerve Growth Factors; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 1; Nociceptive Stimulus; Nociceptors; Pain; Pattern; Peptides; Peripheral; Phosphotransferases; Physiological; Physiology; Plant Roots; Population; Postherpetic neuralgia; Preparation; Property; Proteins; Range; Research; Research Personnel; Resiniferatoxin; Rhizotomy procedure; Role; S100A12 gene; Signal Transduction; Skin; Spinal Cord; Spinal nerve structure; Stimulus; Structure; System; Thermal Hyperalgesias; Time; base; behavior test; day; dorsal horn; foot; heat injury; human S100A12 protein; inflammatory pain; inhibitor/antagonist; keratinocyte; killings; multidisciplinary; nerve injury; neuronal cell body; neurturin; novel; painful neuropathy; prevent; programs; receptive field; reinnervation; response; sciatic nerve; size; small molecule; spinal nerve posterior root

DESCRIPTION (provided by applicant): The present proposals are based on three unifying postulates: that spontaneous activity in a population of C fiber nociceptors is capable of driving neuropathic pain; that the nociceptors responsible for driving neuropathic pain include TrkA-positive nociceptors that have received excessive amounts of nerve growth factor (NGF); and that this excessive NGF can be derived either from collateral sprouting of uninjured nociceptors into denervated regions of the skin. Thus degeneration and loss of neighboring nerve fibers will be sufficient to result in this excessive NGF signaling in the intact nerve fibers. The proposed studies represent a multidisciplinary collaborative effort, with new measures of electrophysiological changes, new models of selective nociceptor injury, and a new genetically engineered mouse in which a TrkA receptor kinase mutation is "knocked-in" so that the TrkA is blocked in its signaling by a small molecule inhibitor, 1NMPP1 that has no effect on wild-type TrkA. We find that administration of the inhibitor eliminates CGRP+ nociceptors from the skin of the hindfoot within 8 days, leaving only the Ret+ positive nociceptors. This preparation will allow assessment of the physiology and behavior produced by the Ret+ in isolation. We also find that these mice have markedly blunted pain behaviors in models on inflammatory pain (CFA) and neuropathic pain (L5 spinal nerve ligation). These studies will define the role of TrkA-positive neurons in the generation of neuropathic pain. We have established the methodologic requirements to carry out all aspects of this research in mice, including physiologic measures of activity- dependent changes in C fiber conduction and behavioral testing for mechanical and thermal hyperalgesia. We have also developed a new system for examining collateral sprouting in the mouse hindfoot, using sparing of the saphenous nerve. The proposed data will have implications for understanding and treating not just pain in partial nerve injuries, but painful neuropathies such as diabetes, causalgia, and postherpetic neuralgia.

描述（由申请人提供）：目前的建议基于三个统一的假设：C纤维伤害感受器的自发活动能够驱动神经性疼痛；负责驱动神经性疼痛的伤害感受器包括收到过量神经生长因子（NGF）的TRKA阳性伤害感受器；而且，这种过多的NGF可以通过将未受伤的伤害感受器的附带发芽衍生成皮肤的未受伤的区域。因此，邻近神经纤维的退化和丧失将足以导致完整的神经纤维中这种过多的NGF信号传导。拟议的研究代表了多学科的协作努力，其新的电生理学变化措施，选择性伤害感受器损伤的新模型以及一种新的基因工程鼠标，其中TRKA受体激酶突变被“敲入”，以便TRKA在其信号中被小分子抑制剂抑制作用，而无需效应。我们发现，抑制剂的给药消除了8天内从后足的皮肤上消除CGRP+伤害感受器，仅留下RET+阳性伤害感受器。此准备将允许评估RET+孤立产生的生理和行为。我们还发现，这些小鼠在炎症性疼痛（CFA）和神经性疼痛（L5脊神经结扎）的模型中显着钝性疼痛行为。这些研究将定义TRKA阳性神经元在神经性疼痛产生中的作用。我们已经建立了在小鼠中进行这项研究的各个方面的方法学要求，包括在C纤维传导和机械和热痛觉过敏的C纤维传导和行为测试中的生理测量。我们还开发了一种新的系统，用于使用隐性神经的保留，以检查小鼠后脚的侧支发芽。所提出的数据将对理解和治疗部分神经损伤的疼痛有影响，而且对疼痛的神经病（例如糖尿病，因果痛和骨性神经痛）有影响。