Non-Immobilizing Inhalational Anesthetic-Like Compounds

Abstract

Nonimmobilizing, inhalational anesthetic-like compounds are experimental agents developed as a tool to investigate the mechanism of action of general anesthetics. Clinically used for more than 150 years, general anesthesia has until now defied all attempts to formulate a theory of its mechanisms that would link, in an uninterrupted logical chain, observations on the molecular level—via effects on the cellular and network levels—to the in vivo phenomenon. Nonimmobilizers, initially termed nonanesthetics, are substances that disobey the Meyer-Overton rule. Theoretically, in appropriately designed experiments, nonanesthetics can serve as a type of Ockham’s razor to separate important from irrelevant observations: processes that, at comparable concentrations, are affected to a similar degree by inhalational anesthetics and by nonanesthetics, do not contribute to anesthesia (the nonanesthetic algorithm). In practice, however, this appealing algorithm has been rather difficult to apply. On one hand, nonanesthetics are not inert on the behavioral level: they cause, inter alia, amnesia. This discovery required not only the introduction of the more precise term “nonimmobilizers,” but also excluded one important component of anesthesia, i.e., amnesia, from application of the algorithm. On the other hand, compared to inhalational anesthetics, nonimmobilizers interact with relatively few molecular targets, also limiting the usefulness of the nonimmobilizer algorithm. Nevertheless, nonimmobilizers have not only yielded useful results but can, by virtue of those very properties that make them less than ideal for anesthesia research, be used as experimental tools in the neurosciences far beyond anesthetic mechanisms.