Reduced sensitivity to ketamine and pentobarbital in mice lacking the N-methyl-D-aspartate receptor GluRε1 subunit
Reduced sensitivity to ketamine and pentobarbital in mice lacking the N-methyl-D-aspartate receptor GluRε1 subunit
复制标题
DOI：
10.1213/01.ane.0000131729.54986.30
复制
发表时间：
2004-10-01
影响因子：
5.7
通讯作者：
Sakimura, K
中科院分区：
文献类型：
--
作者：
Petrenko, AB;Yamakura, T;Sakimura, K
氯胺酮是一种静脉麻醉剂，具有 N-甲基-D-天冬氨酸受体 (NMDAR) 阻断特性。然而，目前尚不清楚氯胺酮的全身麻醉作用是否主要通过阻断 NMDAR 介导。功能性 NMDAR 由 GluRzeta1 (NR1) 亚基与 GluRepsilon (GluRepsilon1-4; NR2A-D) 亚基组装而成，赋予天然 NMDAR 独特的性质。我们假设缺乏 GluRepsilon1（一种丰富且在出生后普遍表达的 NMDAR 亚基）的动物可能对氯胺酮的作用具有抵抗力。在这里，我们评估了翻正反射以确定腹膜内给予 GluRepsilon1 敲除小鼠的氯胺酮的全身麻醉/催眠效力，并将这些结果与野生型小鼠的结果进行比较。突变小鼠对氯胺酮的抵抗力比对照小鼠更强。出乎意料的是，突变小鼠对戊巴比妥的抵抗力也更强，人们认为戊巴比妥在临床相关浓度下不会与 NMDAR 相互作用。尽管这些数据并没有消除 NMDAR GluRepsilon1 亚基参与氯胺酮麻醉/催眠介导的可能性，但它们表明解释基因敲除动物模型中麻醉敏感性改变的困难。
Ketamine is an IV anesthetic with N-methyl-D-aspartate receptor (NMDAR)-blocking properties. However, it is still unclear whether ketamine's general anesthetic actions are mediated primarily via blockade of NMDAR. Functional NMDARs are composed by the assembly of a GluRzeta1 (NR1) subunit with GluRepsilon (GluRepsilon1-4; NR2A-D) subunits, which confer unique properties on native NMDARs. We hypothesized that animals deficient in GluRepsilon1, an abundant and ubiquitously postnatally expressed NMDAR subunit, might be resistant to the effects of ketamine. Here, we evaluated a righting reflex to determine the general anesthetic/hypnotic potency of ketamine administered intraperitoneally to GluRepsilon1 knockout mice and compared these results with those for wild-type mice. Mutant mice were more resistant to ketamine than control mice. Unexpectedly, mutant mice were also more resistant to pentobarbital, which is thought not to interact with NMDAR at clinically relevant concentrations. Although these data in no way eliminate the possibility of the involvement of the NMDAR GluRepsilon1 subunit in mediation of ketamine anesthesia/hypnosis, they suggest the difficulties with interpretation of altered anesthetic sensitivity in knockout animal models.