Mechanisms of Spinally-Mediated Hyperalgesia in Diabetes

糖尿病中脊髓介导的痛觉过敏的机制

• 批准号: 6728280
• 负责人: NIGEL A. CALCUTT
• 金额: $ 26.12万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6728280
• 关键词: active sites; behavior test; diabetes mellitus; diabetic neuropathy; disease /disorder etiology; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; hormone biosynthesis; hormone regulation /control mechanism; hyperalgesia; immunocytochemistry; laboratory rat; microdialysis; prostaglandin endoperoxide synthase; prostaglandins; sensory mechanism; spinal cord; statistics /biometry; substance P; western blottings; active sites; behavior test; diabetes mellitus; diabetic neuropathy; disease /disorder etiology; disease /disorder model; enzyme activity; enzyme linked immunosorbent assay; hormone biosynthesis; hormone regulation /control mechanism; hyperalgesia; immunocytochemistry; laboratory rat; microdialysis; prostaglandin endoperoxide synthase; prostaglandins; sensory mechanism; spinal cord; statistics /biometry; substance P; western blottings

DESCRIPTION (provided by applicant): Diabetes mellitus is a serious and widespread disease in the western world. Neuropathy is the most common of the complications associated with protracted diabetes and the most notable presentation in many patients is some form of abnormal pain perception. This may range from continuous or episodic spontaneous pain to exaggerated pain in response to a mildly painful (hyperalgesia) or innocuous (allodynia) stimulus. The mechanisms underlying painful diabetic neuropathy are not known and there is no targeted therapy available, so that treatment is often restricted to sedatives that impede normal daily function. The objective of this research proposal is to investigate the etiology of sensory dysfunction using the diabetic rat model and cells grown in conditions of elevated glucose. Our previous findings show that diabetic rats exhibit behavioral indices of hyperalgesia and allodynia. This includes a protracted response to spinal delivery of substance P, suggesting that there is a component to hyperalgesia that lies beyond the peripheral nervous system. We have produced preliminary data that shows an increase in spinal levels of the enzyme cyclooxygenase-2 (COX-2), which has been implicated in a number of neuropathic pain states by its ability to produce prostaglandins. Our primary hypothesis is that hyperglycemia induces COX-2 protein and activity in the spinal cord, which leads to exaggerated prostaglindin release in response to sensory input and thereby promotes a spinally mediated hyperalgesia. We will test this hypothesis using diabetic rats exposed to the noxious sensory stimuli of either paw formalin injection or intrathecal excitatory neurotransmitters and make measurements using a variety of behavioral, morphologic, physiologic, biochemical and molecular techniques. We will also use selective pharmacologic agents to define the etiology of increased COX-2 expression in diabetic rats and also in cultured spinal cells (astrocytes and neurons). It is hoped that these studies will prompt development of therapeutics targeted at preventing or alleviating painful diabetic neuropathy.

描述（由申请人提供）：糖尿病是西方世界的一种严重而普遍的疾病。神经病是与旷日持久的并发症中最常见的并发症，在许多患者中最明显的表现是某种形式的异常疼痛感知。这可能从连续或情节的自发性疼痛到响应轻度疼痛（痛觉过敏）或无害（异常性异常）刺激的夸张疼痛。尚不清楚疼痛糖尿病神经病的基础机制，也没有可用的靶向治疗，因此治疗通常仅限于阻碍正常日常功能的镇静剂。这项研究建议的目的是使用糖尿病大鼠模型和在葡萄糖升高的条件下生长的细胞研究感觉功能障碍的病因。我们以前的发现表明，糖尿病大鼠表现出痛觉过敏和异常性疾病的行为指数。这包括对P脊柱递送P的长期反应，这表明Hypergeria的成分超出了周围神经系统。我们已经产生了初步数据，该数据显示了酶环氧酶-2（COX-2）的脊柱水平升高，这与许多神经性疼痛状态有关，其产生前列腺素的能力与许多神经性疼痛态有关。我们的主要假设是高血糖在脊髓中诱导COX-2蛋白和活性，从而导致夸张的前列腺素释放，以响应感官输入，从而促进了跨度介导的Hypergersia。我们将使用暴露于PAW福尔马林注射或鞘内兴奋性神经递质的有害感觉刺激的糖尿病大鼠进行检验，并使用多种行为，形态学，生理学，生物化学和分子技术进行测量。我们还将使用选择性药理学剂来定义糖尿病大鼠以及培养的脊髓细胞（星形胶质细胞和神经元）中COX-2表达增加的病因。希望这些研究能够促进针对预防或减轻疼痛糖尿病神经病的治疗剂的发展。