GENERAL ANESTHETICS& BRAIN N-METHYL-ASPARTATE RECEPTORS

普通麻醉药

基本信息

批准号：
3307871
负责人：
LAURA C DANIELL
金额：
$ 9.1万
依托单位：
AUGUSTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-30 至 1994-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/3307871
关键词：
NMDA receptors aminoacid inhibitor anesthetics brain metabolism calcium flux chemical structure function computer data analysis dosage drug interactions gas chromatography gene expression general anesthesia inhibitor /antagonist laboratory mouse neurochemistry neuropharmacology tissue /cell culture

项目摘要

The specific sites at which general anesthetics act are unknown. However, we recently showed that 1) low concentrations of several clinically useful general anesthetics inhibit responses produced by excitatory brain N-methyl-D-aspartate (NMDA) receptors, and 2) NMDA receptor antagonists increase acute behavioral sensitivity to general anesthetics. Our results are consistent with the idea that brain NMDA receptors are a specific site acted upon by general anesthetics and that their inhibitory effects on NMDA receptors play a major role in the production of general anesthesia. Therefore, the hypothesis of this proposal is that anesthesia is produced, in part, by inhibition of the function of brain NMDA receptors. In the proposed studies, the effects of general anesthetics on NMDA-stimulated increases in intracellular calcium concentrations (Cai) will be determined in brain vesicles. Structure-activity relationships and correlations between inhibition of NMDA receptor responses in brain vesicles in vitro and the ability of NMDA receptor antagonists to increase general anesthetic potency in vivo will be examined. Possible mechanisms of general anesthetic inhibition of NMDA responses including action at an allosteric or channel blocking site of the NMDA receptor and/or alteration of the kinetics of receptor activation and inactivation will be distinguished. This study will increase our understanding of the role of NMDA receptors in anesthesia and may aid in the development of novel anesthetic agents specifically targeted to receptor sites mediating anesthesia.

一般麻醉法的特定站点尚不清楚。但是，我们最近表明1）低浓度的几个临床上有用的一般麻醉抑制了由兴奋性脑N-甲基-D-天冬氨酸（NMDA）受体和2）NMDA 受体拮抗剂提高了对一般的急性行为敏感性麻醉药。我们的结果与脑NMDA的想法一致受体是由全身麻醉药作用的特定部位，它们对NMDA受体的抑制作用在全身麻醉的产生。因此，这个假设提议是，通过抑制部分进行麻醉脑NMDA受体的功能。在拟议的研究中，这些影响 NMDA刺激的一般麻醉药在细胞内增加钙浓度（CAI）将在脑囊泡中确定。结构活动关系和抑制之间的相关性 NMDA受体反应在体外脑囊泡和 NMDA受体拮抗剂增加体内普通麻醉效力将被检查。一般麻醉抑制的可能机制 NMDA的响应，包括在变构或通道阻塞处的动作 NMDA受体的位点和/或受体动力学的改变激活和灭活将被区分。这项研究会增加我们对NMDA受体在麻醉中的作用的理解并可能有助于开发新型麻醉剂针对介导麻醉的受体部位。