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: 6394320
• 负责人: ALICE A LARSON
• 金额: $ 26.45万
• 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/6394320
• 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（摘自申请书）：