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：(申请人摘要) 这是一份申请K奖(研究职业发展)的申请表 奖项)。申请人是一名麻醉师，他对 谷氨酸与NMDA谷氨酸递质系统的作用研究 在伤害性感受和认知功能方面，长期目标是 开发更好的治疗方法来管理慢性疼痛- -利用独一无二的止痛特性的方法 NMDA拮抗剂，同时避免这些药物的严重副作用 包括精神病和认知障碍。申请人有 被选为她的主要赞助人约翰·奥尔尼，医学博士，精神病学家和 神经学家，谷氨酸领域的先驱 过去30年的研究档案。她还将由以下机构共同赞助 John Newcomer博士，医学博士，一位知名的临床研究员， 攻读与申请人职业生涯相关的临床研究 目标。因此，尽管 所有申请都与动物研究有关，这些研究将在 在Olney博士的指导下，申请者将同时合作 与Newcomer博士一起进行人体研究，这将提供培训和 在未来开展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，即 如下：最近的证据表明谷氨酸在脑内是一种递质 NMDA谷氨酸拮抗剂的伤害性通路及文献 受体可以缓解神经病理性疼痛(NPP)，这是一种 对其他已知的止痛药无反应。然而，NMDA拮抗剂 有潜在的严重副作用，包括有毒的退化 皮质神经元和精神病、认知和运动障碍 被认为与体内乙酰胆碱(ACh)的过度释放有关 大脑皮层。奥尔尼博士和他的同事们已经发现， 药物类别，包括a2肾上腺素能激动剂，如可乐定， 能抑制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 可乐定不仅可以抑制这些副作用，还可以增强NPP- NMDA拮抗剂MK801的缓解作用。申请人提出建议 对这些发现进行后续研究，旨在进一步 澄清涉及的机制并确定特定的NMDA 拮抗剂和a2肾上腺素能激动剂联合使用 既能提供高度的安全性，又能极大地缓解核电厂的压力 在动物研究中，最终目标是测试安全性和 这一治疗方案在人类疼痛诊所的疗效 布景。