PSYCHOTIC AND ANALGESIC ACTIONS OF NMDA ANTAGONISTS

NMDA 拮抗剂的精神和镇痛作用

• 批准号: 6342239
• 负责人: Vesna Jevtovic-Todorovic
• 金额: $ 7.91万
• 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 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6342239
• 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：（申请人摘要） 这是一份 K 奖（研究职业发展 奖）。 申请人是一名麻醉师，对以下领域感兴趣 研究谷氨酸和 NMDA 谷氨酸递质系统的作用 伤害感受和认知功能，长期目标是 开发更好的治疗方法来管理慢性疼痛 - 利用独特的镇痛特性的方法 NMDA 拮抗剂，同时避免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 chosen for her primary sponsor John Olney, MD, a psychiatrist and neuroscientist who has been a pioneering leader in the glutamate 过去30年的研究归档。 她还将联合赞助 Dr. John Newcomer, MD, an established clinical investigator who is pursuing clinical studies that are relevant to the applicant's career 目标。 因此，尽管本文中描述的研究项目 申请均与将在下进行的动物研究有关 Olney博士的指导，申请人将同时合作 with Dr. Newcomer on human studies which will provide the training and expertise required to launch her own clinical studies in the future. 申请人的研究解决了一个紧迫的临床问题： follows: Recent evidence implicates glutamate as a transmitter in NMDA 谷氨酸拮抗剂的伤害感受途径和文献 受体可以缓解神经性疼痛（NPP），这是一种 对其他已知的镇痛药没有反应。 然而，NMDA 拮抗剂 有潜在的严重副作用，包括毒性变性 cortical neurons and psychotic, cognitive and motor disturbances that are thought to relate to excessive release of acetylcholine (ACh) in the 大脑皮层。 奥尔尼博士和同事发现，某些 classes of drugs, including a2 adrenergic agonists such as clonidine, can suppress the ACh-releasing action of NMDA antagonists while also 抑制其神经毒性副作用。 申请人发现 clonidine not only suppresses these side effects but enhances the NPP- NMDA 拮抗剂 MK801 的缓解作用。申请人提出 to follow up these findings with additional studies aimed at further 澄清所涉及的机制并确定具体的 NMDA antagonist and a2 adrenergic agonists which, when used in combination can provide both a high degree of safety and superior relief from NPP 在动物研究中，最终目标是测试安全性和 therapeutic efficacy of this treatment regimen in a human pain clinic 环境。