Firestone L L, Sauter J F, Braswell L M, Miller K W
Anesthesiology. 1986 Jun;64(6):694-702. doi: 10.1097/00000542-198606000-00004.
The molecular mechanisms by which general anesthetics act on postsynaptic membranes can only be worked out in a highly purified, homogeneous system. The nicotinic acetylcholine receptor-rich membranes from the electric tissue of Torpedo californica are currently the only postsynaptic membranes that fulfill this condition. Is this peripheral synapse acted on with a pharmacologic specificity similar to that for general anesthesia, and how much less sensitive is it to anesthetic action than the unknown central site? To answer these questions, the authors studied the effects of 13 anesthetic compounds, including volatile general anesthetics, alkanols, and urethane, on the equilibrium binding of 3H-acetylcholine to these nicotinic receptors. As the anesthetic concentration was raised, all the agents first increased acetylcholine binding steeply and then, with few exceptions, decreased it again at higher concentrations. Anesthetics increased acetylcholine binding by decreasing acetylcholine's dissociation constant without changing the Hill coefficient or the number of sites. To a first approximation, the relative ability of these agents to increase 3H-acetylcholine binding parallels that of anesthesia in vivo as predicted by the Meyer-Overton lipid solubility rule. On average, they produced half maximal increases in acetylcholine binding (EC50) at about four times the concentration that causes loss of righting reflex in one-half of a group of animals (ED50). However, a few agents deviated from this relationship. They were the agents with greatest general anesthetic potency in both the volatile anesthetic series (thiomethoxyflurane) and the normal alcohol series (octanol), and required up to 17 times their ED50s to achieve a half effect on acetylcholine binding. Although the concentrations required were high, these effects were reversible.(ABSTRACT TRUNCATED AT 250 WORDS)
全身麻醉药作用于突触后膜的分子机制只能在高度纯化的均匀系统中得以阐明。目前，来自加州电鳐电组织的富含烟碱型乙酰胆碱受体的膜是唯一满足这一条件的突触后膜。这种外周突触对麻醉药的反应是否具有与全身麻醉相似的药理学特异性，以及它对麻醉作用的敏感性比未知的中枢部位低多少？为了回答这些问题，作者研究了13种麻醉化合物，包括挥发性全身麻醉药、链烷醇和氨基甲酸乙酯，对3H-乙酰胆碱与这些烟碱型受体平衡结合的影响。随着麻醉药浓度的升高，所有药物首先急剧增加乙酰胆碱的结合，然后，除少数例外，在更高浓度时又使其降低。麻醉药通过降低乙酰胆碱的解离常数而不改变希尔系数或位点数量来增加乙酰胆碱的结合。初步估算，这些药物增加3H-乙酰胆碱结合的相对能力与迈耶-奥弗顿脂质溶解度规则预测的体内麻醉作用相似。平均而言，它们在使一组动物半数失去翻正反射的浓度（ED50）的约四倍时产生乙酰胆碱结合的半数最大增加（EC50）。然而，有几种药物偏离了这种关系。它们是挥发性麻醉药系列（硫甲氧基氟烷）和正醇系列（辛醇）中全身麻醉效力最大的药物，需要高达其ED50的17倍才能对乙酰胆碱结合产生半数效应。尽管所需浓度很高，但这些效应是可逆的。（摘要截短为250字）
