The Role of Alpha-2 Adrenergic Receptors in the Action of Anesthetics and Analgesics

本研究旨在探讨中枢去甲肾上腺素能系统，特别是α-2肾上腺素能受体在75%一氧化二氮、1.3%氟烷、戊巴比妥钠80 mg/kg(Ip)和吗啡5 mg/kg(Iv)中的作用。选用雄性Wistar大鼠。通过甩尾试验评价药物的镇痛效果，反应潜伏期以最大可能效应的百分比(%MPE)表示。同时观察联合应用α-2肾上腺素能激动剂可乐定(150µg/kg)的效果。用高效液相色谱法和体外受体放射自显影(配基)测定脑和脊髓去甲肾上腺素浓度和α-2受体结合量。我们还观察了应激(钢网捕获)、蓝斑损毁和阿诺酮对一氧化二氮镇痛作用的调节作用。一氧化二氮和吗啡产生镇痛作用(%MPE分别为60%和100%)，而氟烷和戊巴比妥钠则无此作用。可乐定对清醒大鼠有镇痛作用(%MPE为20-40%)。当与一氧化二氮合用时，一氧化二氮的镇痛作用持续。氟烷和戊巴比妥钠的镇痛效果(%MPE分别为60-75%和80-100%)。在一氧化二氮镇痛中，蓝斑和脊髓背角去甲肾上腺素浓度降低，[~3H]-可乐定结合量增加。损毁蓝斑可明显减弱一氧化二氮的镇痛作用，而纳洛酮和应激均不能使其减弱。结论：可乐定可产生(或增强)多种药物的镇痛作用，一氧化二氮的镇痛作用可能与其对中枢去甲肾上腺素系统的作用有关，可能是通过激活下行抑制系统和/或通过α-2肾上腺素能受体抑制初级感觉传入神经元。

The present study was designed to examine the role of central noradrenergic system, especially alpha-2 adrenergic receptors in the action of various anesthetics and analgesics;nitrous oxide 75%, halothane 1.3%, pentobarbital 80mg/kg (ip), and morphine 5mg/kg (iv). Male Wistar rats were used. Analgesic effects of drugs were evaluated by the tail-flick test and response latencies were expressed as the percentage of the maximal possible effect (%MPE). Effects of combined use of alpha-2 adrenergic agonist, clonidine (150mug/kg), were also examined. Noradrenaline concentrations and alpha-2 receptor bindings in the brain and spinal cord were measured, using high performance liquid chromatography and "in vitro" receptor autroadiography (ligand ; [_3H]-clonidine). Modulation of analgesic effect of nitrous oxide by a stress (capture in the steel nets), lesion to the locus coeruleus, and anloxone were also examined.Nitrous oxide and morphine produced analgesia (%MPE 60% and 100%, ), but neither halothane nor pentobarbital did. Clonidine produced analgesia (%MPE 20-40%) in the awake rat. When it was comined with nitrous oxide, analgesic effect of nitrous oxide was sustained. With halothane and pentobarbital, it produced analgesia (%MPE 60-75% and 80-100%). In nitrous oxide-induced analgesia, there was a decrease in noradrenaline concentration and an increase in the binding of [_3H]-clonidine in the locus coeruleus and dorsal horn of the spinal cord. Locus coeruleuslesion markedly attenuated nitrous oxide-induced analgesia, while neither naloxone nor stress attenuated it.It is concluded that clonidine produces (or potentiates) analgesic effects of various drugs and that the analgesic effect of nitrous oxide is attributed to the effect on the central noradrenergic system, possibly by an activation of the descending inhibitory system and/or inhibition of the primary sensory afferent neuron via alpha-2 adrenergic receptors.