Selective blockade of N-methyl-d-aspartate channels in combination with dopamine receptor antagonism induces loss of the righting reflex in mice, but not immobility
Selective blockade of N-methyl-d-aspartate channels in combination with dopamine receptor antagonism induces loss of the righting reflex in mice, but not immobility
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DOI：
10.1007/s00213-014-3634-y
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发表时间：
2014
影响因子：
3.4
通讯作者：
Nobuhito Kikuchi;M. Irifune;Y. Shimizu;Keita Yoshida;K. Morita;T. Kanematsu;N. Morioka;Y. Nakata;N. Sakai
中科院分区：
文献类型：
--
作者：
Nobuhito Kikuchi;M. Irifune;Y. Shimizu;Keita Yoshida;K. Morita;T. Kanematsu;N. Morioka;Y. Nakata;N. Sakai
选择性N-甲基-d-天冬氨酸（NMDA）通道阻断剂MK-801在啮齿动物中不引起翻正反射（LORR）的丧失，并刺激儿茶酚胺能（CA能）神经元，在唤醒中起关键作用。方法采用小鼠全身给药方法。为了评估麻醉，使用三种不同的行为：伤害性反应的丧失（在自由移动状态下没有LORR的镇痛），LORR，以及对伤害性刺激的反应（LORR下的不动性）的运动丧失。相比之下，MK-801联合小剂量多巴胺（DA）受体拮抗剂氟哌啶醇（0.2 mg/kg）剂量依赖性地产生LORR，50%有效剂量（ED 50）为1.6 mg/kg（0.9-3.0; 95%置信限），但不产生固定。α2-肾上腺素受体激动剂右美托咪定不仅诱导了MK-801（5 mg/kg）+氟哌啶醇（0.2 mg/kg）给药组动物的镇痛作用，而且还诱导了不动性，然后这些动物失去了翻正反射。不动的ED 50值为0.26（0.10-0.66）mg/kg（不同剂量的右美托咪定加固定剂量的MK-801和氟哌啶醇），约为镇痛的0.09（0.03-0.23）mg/kg（右美托咪定加溶剂生理盐水）的3倍。这可能发生，因为MK-801加氟哌啶醇诱导的LORR抑制疼痛抑制系统。结论MK-801的DA能兴奋作用可能通过阻断NMDA通道而掩盖其LORR效应。
RationaleThe selectiveN-methyl-d-aspartate (NMDA) channel blocker MK-801 is known to induce no loss of the righting reflex (LORR) and to stimulate catecholaminergic (CAergic) neurons in rodents, playing a crucial role in arousal.ObjectivesWe examined whether MK-801 in combination with CA receptor ligands, which inhibit CAergic neuronal activities, could induce anesthesia including LORR.MethodsAll drugs were administered systemically to mice. To assess anesthesia, three different behaviors were used: loss of nociceptive response (analgesia in the free-moving state without LORR), LORR, and loss of movement in response to noxious stimulation (immobility under LORR).ResultsA very large dose of MK-801 (50 mg/kg) induced neither analgesia nor LORR. In contrast, MK-801 in combination with a small dose of the dopamine (DA) receptor antagonist haloperidol (0.2 mg/kg) dose-dependently produced LORR with a 50 % effective dose (ED50) of 1.6 (0.9–3.0; 95 % confidence limit) mg/kg, but not immobility. The α2-adrenoceptor agonist dexmedetomidine induced not only analgesia, but also immobility in animals treated with MK-801 (5 mg/kg) plus haloperidol (0.2 mg/kg), which then lost their righting reflex. The ED50value of 0.26 (0.10–0.66) mg/kg (various doses of dexmedetomidine plus a fixed dose of MK-801 and haloperidol) for immobility was approximately three-fold larger than that of 0.09 (0.03–0.23) mg/kg (dexmedetomidine plus vehicle saline) for analgesia. This may occur, as LORR induced by MK-801 plus haloperidol inhibits the pain suppression system. The other ligands had little or no effect.ConclusionsThe DAergic stimulant actions of MK-801 may mask its LORR effects by NMDA channel blockade.