PSYCHOTIC AND ANALGESIC ACTIONS OF NMDA ANTAGONISTS

NMDA 拮抗剂的精神和镇痛作用

• 批准号: 6137772
• 负责人: Vesna Jevtovic-Todorovic
• 金额: $ 16.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-02-05 至 2003-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137772
• 关键词: Animalia; NMDA receptors; acetylcholine; analgesia; cerebral cortex; clonidine; cognition; drug adverse effect; glutamate receptor; glutamates; inhibitor /antagonist; pain; psychosis

DESCRIPTION: (Applicant's Abstract) This is an application for a K award (Research Career development Award). The applicant is an anesthesiologist who is interested in studying the role of glutamate and the NMDA glutamate transmitter system in nociception and cognitive functions with the long term goal being to develop better therapeutic approaches to the management of chronic pain- -approaches that take advantage of the unique analgesic properties of NMDA antagonists while avoiding the serious side effects of these agents which include psychosis and cognitive impairment. The applicant has chosen for her primary sponsor John Olney, MD, a psychiatrist and neuroscientist who has been a pioneering leader in the glutamate research filed for the past 30 years. She will also be co-sponsored by Dr. John Newcomer, MD, an established clinical investigator who is pursuing clinical studies that are relevant to the applicant's career goals. Therefore, although the research projects described in the application all pertain to animal research that will be performed under Dr. Olney's guidance, the applicant will simultaneously be collaborating with Dr. Newcomer on human studies which will provide the training and expertise required to launch her own clinical studies in the future. The applicant's research addresses a pressing clinical problem as follows: Recent evidence implicates glutamate as a transmitter in nociceptive pathways and documents that antagonists of NMDA glutamate receptors can alleviate neuropathic pain (NPP), a type of pain that is not responsive to other known analgesics. However, NMDA antagonists have potentially serious side effects, including toxic degeneration of cortical neurons and psychotic, cognitive and motor disturbances that are thought to relate to excessive release of acetylcholine (ACh) in the cerebral cortex. Dr. Olney and colleagues have found that certain classes of drugs, including a2 adrenergic agonists such as clonidine, can suppress the ACh-releasing action of NMDA antagonists while also suppressing their neurotoxic side effects. The applicant has found that clonidine not only suppresses these side effects but enhances the NPP- relieving action of the NMDA antagonist, MK801. The applicant proposes to follow up these findings with additional studies aimed at further clarifying the mechanisms involved and identifying specific NMDA antagonist and a2 adrenergic agonists which, when used in combination can provide both a high degree of safety and superior relief from NPP in animal studies, with the eventual goal being to test the safety and therapeutic efficacy of this treatment regimen in a human pain clinic setting.

描述：（申请人的摘要） 这是K奖的申请（研究职业发展 奖）。 申请人是一位对麻醉师感兴趣的麻醉师 研究谷氨酸和NMDA谷氨酸发射机系统的作用 长期目标是伤害感受和认知功能 开发更好的治疗方法来管理慢性疼痛 - - 充分利用了独特的镇痛特性 NMDA拮抗剂，同时避免了这些药物的严重副作用 其中包括精神病和认知障碍。 申请人有 为她的主要赞助商约翰·奥尔尼（John Olney），医学博士，精神科医生和 神经科学家一直是谷氨酸的开创性领导者 过去30年提出的研究。 她还将共同赞助 约翰·纽科尔（John Newcomer）博士，医学博士，一位既定的临床研究者 从事与申请人职业有关的临床研究 目标。 因此，尽管研究项目在 将所有与动物研究有关的应用 奥尔尼博士的指导，申请人将同时合作 在人类研究的新人博士中，将提供培训和 将来需要启动自己的临床研究所需的专业知识。 申请人的研究解决了一个紧迫的临床问题 以下内容：最近的证据暗示谷氨酸作为发射机 NMDA谷氨酸的拮抗剂的伤害性途径和文档 受体可以减轻神经性疼痛（NPP），一种疼痛 对其他已知的镇痛药反应不足。 但是，NMDA拮抗剂 具有潜在的严重副作用，包括 皮质神经元以及精神病，认知和运动障碍 被认为与乙酰胆碱（ACH）过度释放有关 大脑皮层。 奥尔尼博士及其同事发现确定 药物类别，包括A2肾上腺素能激动剂，例如可乐定， 可以抑制NMDA拮抗剂的ACH释放作用 抑制其神经毒性副作用。 申请人发现 可乐定不仅抑制这些副作用，还可以增强NPP 减轻NMDA拮抗剂的动作MK801。申请人提出 跟进这些发现，以进一步的进一步研究 澄清所涉及的机制并确定特定的NMDA 拮抗剂和A2肾上腺素能激动剂，当将 可以提供高度安全性和NPP的卓越缓解 在动物研究中，最终的目标是测试安全性和 该治疗方案在人类疼痛诊所的治疗功效 环境。