NEUROTROPHINS AND AN ANIMAL MODEL OF FIBROMYALGIA

神经营养因子和纤维肌痛动物模型

• 批准号: 6540221
• 负责人: ALICE A LARSON
• 金额: $ 27.23万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-26 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540221
• 关键词: C fiber; disease /disorder model; fibromyalgia; growth factor receptors; hyperalgesia; injection /infusion; kainate; laboratory rat; model design /development; neurotrophic factors; phosphomonoesterases; spinal ganglion; substance P; thiamine

DESCRIPTION (taken from the application): Fibromyalgia syndrome (FMS) is characterized by pain throughout the body (multifocal) with specific areas that are particularly sensitive to pressure. Primary afferent C-fibers are believed to be important in pain transmission. Some C-fibers contain substance P (SP) and are regulated by nerve growth factor (NGF), while others are characterized by the enzyme thiamine monophosphatase (TMPase) and are supported by glial derived neurotrophic factor (GDNF). Consistent with the hypothesis that C-fibers are involved in FMS, the concentrations of SP and NGF in the CSF of these patients are elevated. What initiates this is not known. C-fibers are depolarized by kainic acid, an excitatory amino acid analog. A single i.p. injection of kainic acid increases TMPase stain in the dorsal spinal cord, suggesting sprouting, and produces a persistent (> 12 weeks) decrease in the intensity of mechanical stimulation required to evoke withdrawal responses in rats similar to the lowered threshold of pressure required to produce pain in patients with FMS. Whether kainic acid produces these effects by increasing GDNF or NGF activity along nociceptive pathways is not known. We will test the hypotheses that the mechanical hyperalgesia produced by kainic acid is caused by enhancement of neurotrophic activity that supports C-fibers (NGF and GDNF) which, in turn, enhances proteins associated with these nociceptive pathways. To accomplish this, we will use a rat model (1) to characterize the effect of kainic acid on mechanical nociception using von Frey fibers and grip force; (2) determine whether the content of NGF and GDNF (immunoreactivity) or its receptors (binding) are affected by treatment with kainic acid; (3) to determine whether the application of exogenous NGF or GDNF is sufficient to increase mechanical nociception; (4) to determine whether there is a change in the density of SP- or NkiR immunoreactivity and/or the density of TMPase in the spinal cord or DRG after injection of NGF or GDNF; and (5) to determine whether injection of kainic acid alters either the density of SP- or NKiR-immunoreactivity in the spinal cord or DRG, in a fashion that correlates with its ability to induce mechanical hyperalgesia. These studies will determine whether kainic acid alters neurotrophic activity and nociceptive responses in the rat in a fashion that is consistent with the biochemical and sensory characteristics of FMS. If kainic acid activity proves to be a useful model of FMS, therapeutic options may be more readily developed for this disease.

描述(取自申请表)： 纤维肌痛综合征(FMS)的特征是全身疼痛 (多焦点)具有对压力特别敏感的特定区域。 初级传入C纤维被认为在痛觉传递中起重要作用。 一些C-纤维含有P物质(SP)，并受神经生长因子的调节 (NGF)，而其他的则以硫胺素单磷酸酶为特征 (TMPase)，并由胶质源性神经营养因子(GDNF)支持。 与C-纤维参与FMS的假设一致， 脑脊液中SP和NGF浓度升高。什么 启动者这一点不得而知。C-纤维被红藻氨酸去极化。 兴奋性氨基酸类似物。一个单独的IP地址。注射用红藻氨酸增加 脊髓背侧的TMPase染色，表明正在发芽，并产生 机械刺激强度持续(&gt；12周)下降 在大鼠中引起类似于降低的阈值的戒断反应所需的 FMS患者产生疼痛所需的压力。红藻氨酸是否 通过增加伤害性感受器上的GDNF或NGF活性来产生这些效应 路径尚不清楚。我们将检验这样的假设，即机械 红藻氨酸引起的痛觉过敏是由神经营养增强引起的 支持C纤维(NGF和GDNF)的活动，进而增强 与这些伤害性信号通路相关的蛋白质。为了实现这一目标，我们 将使用一个大鼠模型(1)来表征红藻氨酸对 使用von Frey纤维和握力的机械伤害性感受；(2)确定 NGF和GDNF(免疫反应性)或其受体的含量 (结合)受红藻氨酸处理的影响；(3)确定 外源性NGF或GDNF的应用足以增加机械性能 伤害性感受；(4)确定SP密度是否发生变化- 或NkiR免疫反应和/或脊髓或DRG中TMPase的密度 在注射NGF或GDNF后；以及(5)确定注射 红藻氨酸改变大鼠脑内SP或NKiR免疫反应强度 脊髓或DRG，以与其诱导能力相关的方式 机械性痛觉过敏。这些研究将确定海藻酸是否 在一定程度上改变大鼠的神经营养活性和伤害性反应 这与FMS的生化和感官特性是一致的。如果 红藻氨酸活性被证明是一种有用的FMS模型，治疗选择 可能更容易发展为这种疾病。