Division of Anesthesiology, Niigata University Graduate School of Medical and Dental Sciences, 1-757 Asahimachi, Niigata 951-8510, Japan.
Anesth Analg. 2010 Feb 1;110(2):461-5. doi: 10.1213/ANE.0b013e3181c76e73. Epub 2009 Nov 21.
Until recently, the N-methyl-D-aspartate (NMDA) receptor was considered to possibly mediate the immobility produced by inhaled anesthetics such as isoflurane and nitrous oxide. However, new evidence suggests that the role of this receptor in abolition of the movement response may be less important than previously thought. To provide further evidence supporting or challenging this view, we examined the anesthetic potencies of isoflurane and nitrous oxide in genetically modified animals with established NMDA receptor dysfunction caused by GluRepsilon1 subunit knockout.
The immobilizing properties of inhaled anesthetics in mice quantitated by the minimum alveolar anesthetic concentration (MAC) were evaluated using the classic tail clamp method.
Compared with wild-type controls, NMDA receptor GluRepsilon1 subunit knockout mice displayed larger isoflurane MAC values indicating a resistance to the immobilizing action of isoflurane. Knockout mice were previously shown to have enhanced monoaminergic tone as a result of genetic manipulation, and this increase in MAC could be abolished in our experiments by pretreatment with the serotonin 5-hydroxytryptamine type 2A receptor antagonist ketanserin or with the dopamine D2 receptor antagonist droperidol at doses that did not affect MAC values in wild-type animals. Mutant mice also displayed resistance to the isoflurane MAC-sparing effect of nitrous oxide, but this resistance was similarly abolished by ketanserin and droperidol. Thus, resistance to the immobilizing action of inhaled anesthetics in knockout mice seems to be secondary to increased monoaminergic activation after knockout rather than a direct result of impaired NMDA receptor function.
Our results confirm recent findings indicating no critical contribution of NMDA receptors to the immobility induced by isoflurane and nitrous oxide. In addition, they demonstrate the ability of changes secondary to genetic manipulation to affect the results obtained in global knockout studies.
直到最近，N-甲基-D-天冬氨酸（NMDA）受体被认为可能介导吸入麻醉剂（如异氟烷和一氧化二氮）引起的不动性。然而，新的证据表明，该受体在消除运动反应中的作用可能不如以前认为的那么重要。为了提供进一步支持或挑战这一观点的证据，我们检查了具有 NMDA 受体功能障碍的遗传修饰动物中异氟烷和一氧化二氮的麻醉效能，该功能障碍是由 GluRepsilon1 亚基敲除引起的。
使用经典的尾巴夹法，通过最小肺泡麻醉浓度（MAC）评估吸入麻醉剂在小鼠中的固定特性。
与野生型对照相比，NMDA 受体 GluRepsilon1 亚基敲除小鼠显示出更大的异氟烷 MAC 值，表明对异氟烷的固定作用具有抗性。敲除小鼠先前由于遗传操作而表现出增强的单胺能张力，并且这种 MAC 的增加可以通过预先用 5-羟色胺 2A 受体拮抗剂酮色林或多巴胺 D2 受体拮抗剂氟哌利多处理来消除，这些剂量不会影响野生型动物的 MAC 值。突变小鼠也对异氟烷和一氧化二氮对 MAC 的节省作用具有抗性，但这种抗性也被酮色林和氟哌利多类似地消除。因此，敲除小鼠对吸入麻醉剂固定作用的抗性似乎继发于敲除后单胺能激活增加，而不是 NMDA 受体功能受损的直接结果。
我们的结果证实了最近的发现，表明 NMDA 受体对异氟烷和一氧化二氮诱导的不动性没有关键贡献。此外，它们还表明遗传操作引起的继发变化能够影响全局敲除研究中获得的结果。
