ANALGESIC MECHANISMS IN PATIENTS WITH CHRONIC PAIN

慢性疼痛患者的镇痛机制

• 批准号: 6289666
• 负责人: MITCHELL B MAX
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF DENTAL & CRANIOFACIAL RESEARCH
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6289666
• 关键词: AMPA receptors; NMDA receptors; analgesia; analgesics; capsaicin; chronic disease /disorder; clinical research; clinical trials; dextromethorphan; diabetic neuropathy; drug adverse effect; drug screening /evaluation; human subject; human therapy evaluation; inhibitor /antagonist; kainate; ketamine; nerve injury; neuropharmacology; pain; receptor sensitivity; shingles

The purpose of this project is to elucidate the neural mechanisms and principles of treatment of chronic pain syndromes, with particular attention to the drug treatment of pain caused by nerve injury. Current research is based on observations from animal studies and initial clinical trials with ketamine that neuropathic pain may be largely mediated by CNS excitation of glutamate receptors. Based on the hypothesis that low affinity NMDA channel blockers which bind to the ion channel for only a fraction of a second will cause less impairment of normal CNS function, two clinical trials evaluated dextromethorphan in patients with diabetic neuropathy and post-herpetic neuralgia. Both studies showed that dextromethorphan reduces diabetic but not post-herpetic pain, indicating that chronic treatment with NMDA antagonists is reasonably well-tolerated and relieves pain. Current work examines dextromethorphan in facial neuralgias. Animal studies suggest that another class of glutamate receptors - AMPA/kainate receptors - play a key role in pain perception and neural sensitization. A dose-response evaluation of an investigational AMPA/kainate antagonist in normal volunteers demonstrated a dose-limiting transient visual obscuration, presumably by blockade of these receptors in the visual system. The antagonist (LY293558) reduced pain and hyperalgesia caused by prior injection of intradermal capsaicin by approximately 50% at doses not producing side effects, but had no effect on the perception of thermal and electrical pain stimuli applied to normal skin. This antagonist also reduced pain and hyperalgesia following third molar extraction. These results suggest that AMPA/kainate antagonists may have utility as analgesics in conditions that include a component of sensitization of central neurons. - pain, controlled clinical trial, glutamate, NMDA receptor, AMPA receptor, kainate receptor, phantom limb pain - Human Subjects

该项目的目的是阐明慢性疼痛综合征治疗的神经机制和原理，特别注意神经损伤引起的疼痛的药物治疗。当前的研究基于动物研究和氯胺酮初步临床试验的观察结果，即神经性疼痛可能在很大程度上是由CNS激发谷氨酸受体介导的。基于以下假设：低亲和力NMDA通道阻滞剂仅与离子通道结合仅需一秒钟就会导致正常中枢神经系统功能的损害较小，两项临床试验评估了糖尿病神经病患者的脱铁甲甲苯和治疗后神经疾病。两项研究都表明，右美甲肾脏可减少糖尿病性疼痛，但不能减轻疾病后疼痛，表明用NMDA拮抗剂进行了慢性治疗，耐受耐受性良好并缓解疼痛。当前的工作检查了面部神经痛中的右美甲苯。动物研究表明，另一种类型的谷氨酸受体 - AMPA/海藻酸盐受体 - 在疼痛感知和神经敏化中起关键作用。正常志愿者中研究AMPA/Kainate拮抗剂的剂量反应评估表明，限制剂量的瞬时视觉遮挡，大概是由于视觉系统中这些受体的封锁而进行的。拮抗剂（LY293558）在未产生副作用的剂量时先前注射了皮内辣椒素的疼痛和痛性高过敏症，但对对正常皮肤的热疼痛刺激的感知没有影响。该拮抗剂还减轻了第三摩尔提取后的疼痛和痛觉过敏。这些结果表明，在包括中央神经元的敏化成分的条件下，AMPA/Kainate拮抗剂可能具有效用为镇痛药。 - 疼痛，对照临床试验，谷氨酸，NMDA受体，AMPA受体，海藻酸盐受体，幻影肢体疼痛 - 人类受试者