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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.

全麻药起作用的具体部位尚不清楚。然而，我们最近发现，1)低浓度的几种临床上有用的全身麻醉药抑制由兴奋性脑N-甲基-D-天冬氨酸(NMDA)受体；受体拮抗剂增加对一般药物的急性行为敏感性麻醉剂。我们的结果与大脑NMDA的观点一致受体是由全麻药作用的特定部位，它们对NMDA受体的抑制作用在生产全身麻醉。因此，这一假设有一种观点认为，麻醉的产生部分是通过抑制脑内NMDA受体的功能。在拟议的研究中，这些影响全麻药对NMDA刺激的细胞内钙离子浓度升高的影响将测定脑泡中的钙浓度(CaI)。构效关系及其抑制作用之间的相关性体外培养的脑泡NMDA受体反应及其能力的研究 NMDA受体拮抗剂在体内增加全身麻醉效力将会被检查。全身麻醉抑制的可能机制包括在变构或通道阻断时的作用的NMDA反应 NMDA受体的位置和/或受体动力学的改变激活和停用将被区分开来。这项研究将加深对NMDA受体在麻醉中的作用的了解并可专门帮助开发新型麻醉剂靶向介导麻醉的受体部位。