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本帖最后由 GoalYou 于 2013-1-19 18:58 编辑
【第351篇】多巴胺——促进全身麻醉苏醒的药物
注：第365篇的Editorial Views
Dopamine-enhancing Medications to Accelerate Emergence from General Anesthesia
Benveniste, Helene M.D., Ph.D.*; Volkow, Nora D. M.D.?
Dopaminergic neurotransmission is prominently implicated in emergence from the minimal conscious state,1,2 general anesthesia,3 and in sleep–wake regulation.4 The molecular mechanisms for these effects are still incompletely understood. The anatomical and neurochemical signatures of the dopamine (DA) system for arousal under conditions of general anesthesia are clinically important to understand. First, from a clinical point of view, accurate knowledge of the molecular basis for emergence from general anesthetics with agents for which no specific antagonists exists (i.e., inhalational agents) and for other anesthetic regimens could lead to the development of a range of new drugs specifically designed for rapid emergence. Such therapeutics could perhaps be useful in the future for routine anesthesia practice. For example, rapid arousal of elderly patients undergoing surgical procedures requiring general anesthesia may prove valuable for reducing cognitive dysfunction and/or early delirium postoperatively. Second, a better understanding of the neuronal mechanisms by which DA increases the emergence from anesthesia will also help in the management of patients with DA abnormalities as may be the case for patients with Parkinson disease, schizophrenic patients treated with depot neuroleptics (long-acting dopamine-2 receptor [D2R] antagonists) and drug abusers.
In this issue of ANESTHESIOLOGY, Taylor et al.5 report that the dopamine-1 receptor (D1R) agonist 6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide but not the D2R agonist quinpirole reduces the time to emergence from isoflurane anesthesia in rats by 85% compared with placebo. The authors conclude that selective activation of D1Rs is sufficient to induce emergence from isoflurane general anesthesia and that D2Rs are not needed.5 These new data in the setting of isoflurane anesthesia are intriguing and supplement older data reporting similar findings with phenobarbital anesthesia.6,7 Specifically, Horita et al.7 investigated the effects of a D1R agonist (1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7,8-diol) and a D2R antagonist (raclopride) on duration of phenobarbital anesthesia in rats (administered only 20 min after induction with 40 mg/kg intraperitoneal phenobarbital to reduce pharmacokinetic effects on emergence). They documented that the D1R agonist reduced the time to emergence by approximately 30% and found that this effect could be abolished by a D1R antagonist.7 However, in contrast to the current study,5 Horita et al.7 reported that the D2R antagonist raclopride and atropine also reversed the effect of the D1R agonist. Thus, the findings of Horita et al. suggest that the arousing effects of D1R agonists require the coactivation of these two receptors (D1R and D2R). Interestingly, although nonsignificant, the study by Taylor et al.5 showed decreases in the time from emergence of anesthesia in the rats treated with the D2R agonist quinpirole (from 330 to 189 s) and had their sample (n = 6) been larger, this effect may have been significant. Regardless, it is clear that the effects of the D1R agonist was stronger than that of the D2R agonist (quinpirole), which could reflect in part its effects on D2R autoreceptors that would lead to a decrease in DA release. In the previous study, Horita et al.7 also provide evidence that the dopaminergic effects (driven by D1R but presumably requiring background D2R tone) are mediated by downstream cholinergic effects (because these effects were blocked by atropine). In the context of the importance of D2Rs, Solt et al.3 reported that droperidol (a potent D2 antagonist) abolished the ability of the DA-enhancing drug methylphenidate to accelerate emergence in rats anesthetized with isoflurane, which also strongly suggests that D2Rs are important for anesthesia emergence.
Another intriguing question is which brain pathways mediate the effects of DA in emergence from anesthesia. In general, studies on DA networks have focused mostly on pathways involved with movement (mesostriatal), reward (mesoaccumbens), and cognition (mesocortical), and much less is known about the DA pathways implicated in arousal. Although it is plausible that some or all of these DA pathways participate in arousal, it is also likely that DA mediates its arousing effects through additional brain-wide systems. For example, the orexin/hypocretin lateral hypothalamic nucleus, which mediates arousal and is implicated in narcolepsy, is modulated by both D1R and D2R.8,9 Similarly, the tuberomammillary nucleus, which is involved in the control of wakefulness, signals not only through histamine receptors but also through D1R and D2R.10 In addition, as discussed by Taylor et al.,5 DA neurons in the ventral periaqueductal gray could mediate the effects of DA on the emergence from anesthesia.11 Finally, it is also possible that DA mediates its effects on arousal via thalamic activation.12
Over the past decades, scientists have studied the DA system’s role in cognition, motor behavior, and reward and its disruption in neuropsychiatric diseases. The data of Taylor et al.5 and that of others now highlight the importance of DA in arousal. These findings have direct clinical implications for the practice of anesthesia for they may help direct the development of new medications to accelerate the emergence from anesthesia.
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多巴胺——促进全身麻醉苏醒的药物
多巴胺能神经元与最低意识状态的苏醒、全身麻醉的苏醒以及睡眠-觉醒的调节密切相关。这些作用相关的分子机制还未完全被阐明。了解全麻状态下促进觉醒的多巴胺系统的解剖和神经化学特征十分重要。首先，从临床上看，一些全麻药物没有相应的拮抗剂（例如：吸入麻醉药），了解这些药物和其他麻醉药物全麻苏醒过程精确的分子机制可引领一大批加速苏醒的药物的开发。这些药物可能在将来日常临床工作中发挥作用。例如，老年患者需要全麻手术时，快速苏醒可能会减少术后认知功能障碍和/或早期瞻望。其次，了解多巴胺促进全麻苏醒的神经机制将对多巴胺系统功能异常患者（例如：帕金森病患者、接受镇静剂（长效多巴胺受体-2拮抗剂）治疗的精神分裂患者）以及药物滥用患者的麻醉管理有帮助。
在这一期《Anesthesiology》中，Taylor等人报道多巴胺-1受体（D1R）激动剂（6-chloro-7,8-dihydroxy -3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide）可缩短异氟烷全身麻醉大鼠85%苏醒时间，而D2R激动剂（quinpirole）则不能。文中总结时标明，选择性激动D1R足够促进异氟烷全身麻醉苏醒，而不需要D2R受体参与。这些新的结果十分吸引人，而且对既往有关苯巴比妥麻醉苏醒研究的报道进行补充。Horita等人研究了D1R受体激动剂（1-phenyl-2,3,4,5-tetrahydro-1H-3-benzaze-pine-7,8-diol）和D2R受体拮抗剂（raclopride）在苯巴比妥麻醉大鼠中的作用（在40mg/kg 苯巴比妥腹腔麻醉后20min 进行注射以减少药代动力学效应对觉醒的影响）。他们的研究表明D1R受体激动剂大约可减少30%苏醒时间，而且该作用能够被D1R受体拮抗剂所抵消。然而，与本期文章不同的是，Horita等人报道D2R受体拮抗剂raclopride和aropine同样能够逆转D1R受体激动剂的作用。因此，Horita等人的研究表明D1R受体激动剂促进觉醒的作用需要D1R和D2R的共同作用。有趣的是，尽管作用不显著，Taylor等人的研究表明D2R受体激动剂quinpirole同样能够减少异氟烷全身麻醉的苏醒时间（从330s到189s），而且如果样本量更大一些（n=6），该作用也许更加显著。不管怎样，很明确的是D1R受体激动剂比D2R受体激动剂（quinpirole）具有更强的作用，D2R受体激动剂可能通过作用于D2R自受体导致多巴胺释放减少发挥部分作用。在之前的研究中，Horita等人表明多巴胺能的作用（由D1R受体发挥主要作用，但同时需要D2R的存在）是通过下游的胆碱能递质进行调节（因为这些作用可以被阿托品拮抗）。Solt等人报道，droperidol（一个很强的D2受体拮抗剂）可抑制促进多巴胺释放的药物哌醋甲酯促进异氟烷全身麻醉大鼠的苏醒作用，这同样表明D2R在全麻苏醒中发挥重要作用。
另外一个有趣的问题是，哪些中枢神经系统通路在多巴胺促进麻醉苏醒中发挥作用。通常情况下，有关多巴胺网络的研究集中于运动（mesostriatal亚群）、奖赏（mesoaccumbens亚群）和认知（mesocortical亚群），而关于多巴胺在觉醒中的作用知之甚少。尽管，或许部分或者全部这些通路都与觉醒相关，但是多巴胺递质可能通过中枢神经系统其它的通路发挥作用。例如，可促进苏醒，并且与嗜睡相关的外侧下丘脑分泌食欲素的神经核团可被D1R和D2R受体调节。同样，控制觉醒的结节乳头核不仅与组胺受体相关，而且受D1R和D2R受体调节。此外，同Taylor等人讨论的一样，腹侧中脑导水管周围灰质的多巴胺神经元可能介导多巴胺促进麻醉苏醒的作用。最后，多巴胺可能通过激活丘脑发挥其促进觉醒的作用。
在过去十几年，科学家们已经对多巴胺系统在认知、运动和奖赏以及其在中枢神经系统疾病中的作用进行研究。Taylor等人以及其他人的研究结果强调了多巴胺在觉醒中的作用。这些发现能够对日常麻醉工作具有直接临床意义，并且可能直接促进加速麻醉苏醒药物的开发。 |
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发表于 2013-2-19 12:58:40
