NEUROTROPHINS AND AN ANIMAL MODEL OF FIBROMYALGIA

神经营养因子和纤维肌痛动物模型

基本信息

批准号：
6639625
负责人：
ALICE A LARSON
金额：
$ 28.03万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-07-26 至 2005-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6639625
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

项目摘要

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（摘自应用程序）：纤维肌痛综合征 (FMS) 的特点是全身疼痛（多焦点）具有对压力特别敏感的特定区域。初级传入 C 纤维被认为在疼痛传递中很重要。一些C纤维含有P物质（SP）并受神经生长因子调节 (NGF)，而其他的则以硫胺素单磷酸酶为特征（TMPase）并得到神经胶质源性神经营养因子（GDNF）的支持。与 C 纤维参与 FMS 的假设一致，这些患者脑脊液中 SP 和 NGF 的浓度升高。什么发起这一点尚不清楚。 C 纤维被红藻氨酸去极化，红藻氨酸是一种兴奋性氨基酸类似物。单个 ip。红藻氨酸注射量增加背侧脊髓中的 TMPase 染色表明正在发芽，并产生机械刺激强度持续（> 12 周）降低需要在大鼠中引起类似于降低阈值的戒断反应 FMS 患者产生疼痛所需的压力。是否含有红藻氨酸通过增加伤害感受性的 GDNF 或 NGF 活性来产生这些效果途径未知。我们将测试机械的假设红藻氨酸产生的痛觉过敏是由于神经营养的增强而引起的支持 C 纤维（NGF 和 GDNF）的活动，进而增强与这些伤害感受途径相关的蛋白质。为了实现这一目标，我们将使用大鼠模型 (1) 来表征红藻氨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）或其受体（结合）受到红藻氨酸处理的影响； (3)判断是否外源性 NGF 或 GDNF 的应用足以增加机械伤害感受； (4) 判断SP-的密度是否有变化或 NkiR 免疫反应性和/或脊髓或 DRG 中 TMPase 的密度注射NGF或GDNF后； (5) 判断是否注入红藻氨酸改变 SP 或 NKiR 免疫反应性的密度脊髓或 DRG，其方式与其诱导能力相关机械性痛觉过敏。这些研究将确定红藻氨酸是否以某种方式改变大鼠的神经营养活性和伤害性反应这与FMS的生化和感官特性一致。如果红藻氨酸活性被证明是 FMS、治疗选择的有用模型可能更容易针对这种疾病开发。