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: 2843921
• 负责人: ALICE A LARSON
• 金额: $ 24.96万
• 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/2843921
• 关键词: C fiber; disease /disorder model; fibromyalgia; growth factor receptors; hyperalgesia; injection /infusion; kainate; laboratory rat; model design /development; neuroimmunomodulation; 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（取自应用程序）： 纤维肌痛综合征（FMS）的特征是整个身体疼痛 （多灶）具有对压力特别敏感的特定区域。 据信初级传入C纤维在疼痛传播中很重要。 一些C纤维包含P（SP），并由神经生长因子调节 （NGF），而其他则以硫胺素单磷酸酶为特征 （TMPase），并由神经胶质衍生的神经营养因子（GDNF）支持。 与C纤维参与FMS的假设一致 这些患者CSF中SP和NGF的浓度升高。什么 启动这尚不清楚。 C纤维被海藻酸去极化， 兴奋性氨基酸类似物。一个I.P.海藻酸的注射增加 在背脊髓中的TMPase染色，建议发芽并产生一个 持续（> 12周）机械刺激强度降低 需要在大鼠中引起撤回反应，类似于降低的阈值 在FMS患者中产生疼痛所需的压力。海藻酸是否 通过增加伤害感受的GDNF或NGF活性来产生这些效果 途径尚不清楚。我们将测试机械的假设 海藻酸产生的痛觉过敏是由神经营养的增强引起的 支持C纤维（NGF和GDNF）的活动又增强了 蛋白质与这些伤害性途径相关。为此，我们 将使用大鼠模型（1）来表征海藻酸对 使用冯·弗雷纤维和握力的机械伤害感受； （2）确定 NGF和GDNF的含量（免疫反应性）还是其受体 （结合）受海藻酸治疗的影响； （3）确定是否 外源性NGF或GDNF的应用足以增加机械 伤害感受； （4）确定SP-密度是否有变化 或NKIR免疫反应性和/或脊髓或DRG中TMPase的密度 注射NGF或GDNF后； （5）确定注射是否 海藻酸会改变Sp-或Nkir免疫反应的密度 脊髓或DRG，以与其诱导能力相关的方式 机械痛觉过敏。这些研究将确定海藻酸是否 以大鼠的方式改变大鼠的神经营养活性和伤害性反应 这与FMS的生化和感觉特征一致。如果 事实证明，海藻酸活性是FMS，治疗选择的有用模型 可能更容易为这种疾病开发。