Analgesic Mechanisms in Patients with Chronic Pain

慢性疼痛患者的镇痛机制

• 批准号: 6104588
• 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/6104588
• 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 an initial clinical trial 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. 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. These results suggest that AMPA/kainate antagonists may have utility as analgesics in conditions that include a component of sensitization of central neurons.

该项目的目的是阐明神经 慢性疼痛综合症治疗的机制和原理， 特别注意由 神经损伤。当前的研究基于动物的观察结果 研究和氯胺酮的初步临床试验神经性疗法 CNS激发谷氨酸可能在很大程度上介导疼痛 受体。基于低亲和力NMDA通道的假设 仅一小部分A与离子通道结合的阻滞剂 第二会导致正常CNS功能的损害较小，两个 临床试验评估了糖尿病患者的右美甲苯 神经病变和疱疹后神经痛。两项研究都表明 右美甲肾病可减少糖尿病，但不能减少疱疹后疼痛， 表明用NMDA拮抗剂进行慢性治疗是 合理的耐受性良好并缓解疼痛。动物研究表明 另一类的谷氨酸受体 - AMPA/Kainate受体 - 在疼痛感知和神经敏化中发挥关键作用。一个 研究AMPA/Kainate的剂量反应评估 正常志愿者的拮抗剂表现出剂量限制 瞬态视觉遮挡，大概是通过封锁的 视觉系统中的受体。拮抗剂（LY293558）降低 疼痛和痛觉过敏是由于事先注射 辣椒素在不产生的剂量下约50％ 效果，但对热和电气的感知没有影响 疼痛刺激应用于正常皮肤。这些结果表明 AMPA/Kainate拮抗剂可能具有效用作为镇痛药 包括中央敏化成分的条件 神经元。