Role of endogenous sleep-wake and analgesic systems in anesthesia
Role of endogenous sleep-wake and analgesic systems in anesthesia
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DOI：
10.1002/cne.21685
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发表时间：
2008-06-01
影响因子：
2.5
通讯作者：
Saper, Clifford B.
中科院分区：
文献类型：
--
作者：
Lu, Jun;Nelson, Laura E.;Saper, Clifford B.
γ-氨基丁酸A型受体（GABA（A））增强类的经典麻醉剂（例如，戊巴比妥、水合氯醛、蝇蕈醇和乙醇）产生镇痛和无意识（镇静）。拮抗N-甲基-D-天冬氨酸（NMDA）受体的解离性麻醉剂（例如，氯胺酮、MK-801、美沙芬和苯环己哌啶）产生镇痛作用，但不诱导完全意识丧失。为了了解全身麻醉药引起的意识丧失和镇痛的潜在机制，我们检测了c-Fos蛋白在脑中的表达模式，并将其与全身给予GABA能药物和氯胺酮（临床用于麻醉的剂量）的生理效应相关联。我们发现GABA能药物在脑电图和镇静中主要产生δ活性。与此相反，麻醉剂量的氯胺酮诱导镇静，然后是主动唤醒行为，并产生更快的脑电图在θ范围。与其行为效应一致，氯胺酮诱导Fos在胆碱能、单胺能和食欲素能唤醒系统中表达，并完全抑制促进睡眠的腹外侧视前核（VLPO）中的Fos免疫反应性。与此相反，GABA能药物抑制Fos在相同的唤醒促进系统，但增加了Fos免疫反应神经元的数量在VLPO与清醒的控制动物。所有测试的麻醉剂在脊髓投射去甲肾上腺素能A5-7组中诱导Fos。6-A5-7组的羟基多巴胺损伤或腹外侧导水管周围灰质（APAG）的鹅膏蕈氨酸损伤减弱了两种类型麻醉剂对伤害性热刺激（甩尾试验）的抗伤害性反应。我们假设，睡眠-觉醒行为的神经基质参与了低剂量镇静麻醉剂，中脑脑桥下行去甲肾上腺素能细胞群有助于NMDA受体拮抗剂和GABA（A）受体增强麻醉剂的镇痛作用。
Classical anesthetics of the gamma-aminobutyric acid type A receptor (GABA(A))-enhancing class (e.g., pentobarbital, chloral hydrate, muscimol, and ethanol) produce analgesia and unconsciousness (sedation). Dissociative anesthetics that antagonize the N-methyl-D-aspartate (NMDA) receptor (e.g., ketamine, MK-801, dextromethorphan, and phencyclidine) produce analgesia but do not induce complete loss of consciousness. To understand the mechanisms underlying loss of consciousness and analgesia induced by general anesthetics, we examined the patterns of expression of c-Fos protein in the brain and correlated these with physiological effects of systemically administering GABAergic agents and ketamine at dosages used clinically for anesthesia in rats. We found that GABAergic agents produced predominantly delta activity in the electroen-cephalograin (EEG) and sedation. In contrast, anesthetic doses of ketamine induced sedation, followed by active arousal behaviors, and produced a faster EEG in the theta range. Consistent with its behavioral effects, ketamine induced Fos expression in cholinergic, monoaminergic, and orexinergic arousal systems and completely suppressed Fos immunoreactivity in the sleep-promoting ventrolateral preoptic nucleus (VLPO). In contrast, GABAergic agents suppressed Fos in the same arousal-promoting systems but increased the number of Fos-immunoreactive neurons in the VLPO compared with waking control animals. All anesthetics tested induced Fos in the spinally projecting noradrenergic A5-7 groups. 6-hydroxydopamine lesions of the A5-7 groups or ibotenic acid lesions of the ventrolateral periaqueductal gray matter (APAG) attenuated antinociceptive responses to noxious thermal stimulation (tail-flick test) by both types of anesthetics. We hypothesize that neural substrates of sleep-wake behavior are engaged by low-dose sedative anesthetics and that the mesopontine descending noradrenergic cell groups contribute to the analgesic effects of both NMDA receptor antagonists and GABA(A) receptor-enhancing anesthetics.