The (cid:1) 2 -Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects
The (cid:1) 2 -Adrenoceptor Agonist Dexmedetomidine Converges on an Endogenous Sleep-promoting Pathway to Exert Its Sedative Effects
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背景资料：作者研究了全身麻醉药右美托咪定（一种选择性（cid：1）2 -肾上腺素受体激动剂）的镇静或催眠作用是否激活内源性非快速眼动（NREM）睡眠促进通路。方法：采用免疫组织化学和原位杂交技术检测大鼠脑内促睡眠核团c-Fos的表达。接下来，作者使用（1）鹅膏蕈氨酸诱导的离散病变，（2）大鼠局部和全身给予（cid：2）-氨基丁酸受体A型（GABA A）受体拮抗剂gabazine，或（3）（cid：1）2 -肾上腺素受体拮抗剂阿替美唑，以及（4）小鼠（cid：1）2A -肾上腺素受体的基因突变来扰乱这些通路。结果如下：右美托咪定在大鼠中诱导与正常NREM睡眠期间观察到的c-Fos表达的定性相似模式，即蓝斑（LC）和结节乳头核（TMN）减少，腹外侧视前核（VLPO）增加。这些变化被阿替美唑减弱，并且在缺乏功能性（cid：1）2A -肾上腺素受体的小鼠中未观察到，这些小鼠不具有功能性（cid：1）2A -肾上腺素受体。结论：作者提出内源性睡眠通路在原因上参与了右美托咪定诱导的镇静;右美托咪定的镇静机制涉及抑制LC，从而抑制VLPO放电。VLPO末端GABA释放的增加抑制了TMN放电，这是镇静反应所必需的。
Background: The authors investigated whether the sedative, or hypnotic, action of the general anesthetic dexmedetomidine (a selective (cid:1) 2 -adrenoceptor agonist) activates endogenous non- rapid eye movement (NREM) sleep-promoting pathways. Methods: c-Fos expression in sleep-promoting brain nuclei was assessed in rats using immunohistochemistry and in situ hybridization. Next, the authors perturbed these pathways us- ing (1) discrete lesions induced by ibotenic acid, (2) local and systemic administration of (cid:2) -aminobutyric acid receptor type A (GABA A ) receptor antagonist gabazine, or (3) (cid:1) 2 -adrenoceptor antagonist atipamezole in rats, and (4) genetic mutation of the (cid:1) 2A -adrenoceptor in mice. Results: Dexmedetomidine induced a qualitatively similar pattern of c-Fos expression in rats as seen during normal NREM sleep, i.e. , a decrease in the locus ceruleus (LC) and tuberomammillary nucleus (TMN) and an increase in the ventrolateral preoptic nucleus (VLPO). These changes were attenuated by atipamezole and were not seen in mice lacking functional (cid:1) 2A - adrenoceptors, which do not Conclusions: The authors propose that endogenous sleep pathways are causally involved in dexmedetomidine-induced sedation; dexmedetomidine’s sedative mechanism involves in- hibition of the LC, which disinhibits VLPO firing. The increased release of GABA at the terminals of the VLPO inhibits TMN firing, which is required for the sedative response.