Alkire Michael T, McReynolds Jayme R, Hahn Emily L, Trivedi Akash N
Department of Anesthesiology, Center for the Neurobiology of Learning and Memory, University of California, Irvine, California, USA.
Anesthesiology. 2007 Aug;107(2):264-72. doi: 10.1097/01.anes.0000270741.33766.24.
Neuronal nicotinic acetylcholine receptors are both potently inhibited by anesthetics and densely expressed in the thalamus. Brain imaging shows that thalamic activity suppression accompanies anesthetic-induced unconsciousness. Therefore, anesthetic-induced unconsciousness may involve direct antagonism of thalamic nicotinic receptors. The authors test this by separately attempting to block or enhance anesthetic-induced loss of righting in rats using intrathalamic microinjections of nicotine or its antagonist.
Rats were implanted with a cannula aimed at the thalamus or control locations. A week later, loss of righting was induced using sevoflurane (1.4 +/- 0.2%). A dose-parameter study (n = 35) first identified an optimal intrathalamic nicotine dose associated with arousal. Subsequently, this dose was used to pinpoint the thalamic site mediating the arousal response (n = 107). Finally, sevoflurane righting dose and response specificity were assessed after blocking nicotinic channels with intrathalamic mecamylamine pretreatment (n = 8) before nicotine challenge.
Nicotine (150 microg/0.5 microl over 1 min) was the optimal arousal dose, because lower doses (75 microg) were ineffective and higher doses (300 microg) often caused seizures. Nicotine temporarily restored righting and mobility in animals when microinjections involved the central medial thalamus (P < 0.0001, chi-square). Righting occurred despite continued sevoflurane administration. Intrathalamic mecamylamine pretreatment did not lower the sevoflurane dose associated with loss of righting, but prevented the nicotine arousal response.
The reversal of unconsciousness found here with intrathalamic microinfusion of nicotine suggests that suppression of the midline thalamic cholinergic arousal system is part of the mechanism by which anesthetics produce unconsciousness.
神经元烟碱型乙酰胆碱受体既受到麻醉剂的强烈抑制，又在丘脑密集表达。脑成像显示，丘脑活动抑制伴随着麻醉诱导的意识丧失。因此，麻醉诱导的意识丧失可能涉及丘脑烟碱受体的直接拮抗作用。作者通过在大鼠丘脑内微量注射尼古丁或其拮抗剂，分别尝试阻断或增强麻醉诱导的翻正反射丧失，来对此进行测试。
给大鼠植入一根针对丘脑或对照部位的套管。一周后，使用七氟醚（1.4±0.2%）诱导翻正反射丧失。一项剂量参数研究（n = 35）首先确定了与觉醒相关的最佳丘脑内尼古丁剂量。随后，使用该剂量来确定介导觉醒反应的丘脑部位（n = 107）。最后，在尼古丁激发前，通过丘脑内美加明预处理阻断烟碱通道后（n = 8），评估七氟醚翻正剂量和反应特异性。
尼古丁（1分钟内150微克/0.5微升）是最佳觉醒剂量，因为较低剂量（75微克）无效，而较高剂量（300微克）常引起癫痫发作。当微量注射涉及丘脑中央内侧时，尼古丁能暂时恢复动物的翻正反射和活动能力（P < 0.0001，卡方检验）。尽管持续给予七氟醚，仍出现了翻正反射。丘脑内美加明预处理并未降低与翻正反射丧失相关的七氟醚剂量，但阻止了尼古丁引起的觉醒反应。
此处通过丘脑内微量注射尼古丁发现意识丧失的逆转，表明中线丘脑胆碱能觉醒系统的抑制是麻醉剂产生意识丧失机制的一部分。
