Anesthetic and nonanesthetic halogenated volatile compounds wave dissimilar activities on nicotinic acetylcholine receptor desensitization kinetics

Background: The Meyer-Overton rule predicts that an anesthetic's potency will correlate with its oil solubility. A group of halogenated volatile compounds that disobey this rule has been characterized. These compounds do not induce anesthesia in rats at partial pressures exceeding those predicted by the Meyer-Overton rule to be anesthetic. The observation that potentiation of GABA(A) receptor responses by anesthetic and nonanesthetic halogenated volatile compounds correlates with their abilities to induce general anesthesia suggests that this receptor is involved in the mechanism of general anesthesia. However, the GABA(A) receptor is only one member of a superfamily of structurally similar ligand-gated ion channels, This study compares the actions of both anesthetic and nonanesthetic halogenated volatile compounds on another member of this superfamily of receptors, the nicotinic acetylcholine receptor (nAcChoR). Methods: The actions of both anesthetic and nonanesthetic compounds on desensitization kinetics were characterized from the time-dependent binding of the fluorescent acetylcholine analogue, Dns-C-6-Cho, to the nAcChoR. Results: At concentrations predicted by the Meyer-Overton rule to be equianesthetic, the anesthetics isoflurane and enflurane were significantly more effective than the nonanesthetics 1,2-dichlorohexanuorocyclobutane and 2,3-dichlorooctafluorobutane in enhancing the fraction of receptors preexisting in the slow desensitized state and increasing the apparent rates of agonist-induced fast and slow desensitization. Conclusions: The potencies with which anesthetic and nonanesthetic compounds enhance desensitization kinetics in the nAcChoR parallel their in vivo anesthetic potencies. These results support the use of desensitization of the nAcChoR as a mechanistic model for studies of general anesthesia and suggest that an insensitivity to nonanesthetic compounds may be a feature common to members of the superfamily of ligand-gated ion channels.