GENERAL ANESTHETICS& BRAIN N-METHYL-ASPARTATE RECEPTORS

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。

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.