Contradicting a Unitary Theory of General Anesthetic Action: a History of Three Compounds from 1901 to 2001

The introduction of diethyl ether, chloroform, and nitrous oxide into clinical practice over 150 years ago revolutionized medicine and surgery. However, despite a long period of clinical use, it has been difficult to elucidate the molecular basis for general anesthesia. Even today this question continues to be a source of active inquiry and debate. Although investigators in the last half of the nineteenth century proposed various theories for the actions of anesthetics, the first ‘modern’ theory for general anesthetic action came from the independent works of Meyer and Overton. The observation by Meyer and Overton, supported by extensive experimental investigation, was that the anesthetic potency of certain compounds (‘narcotics’ in the older terminology) varied in direct proportion to the partition coefficient in a lipid solvent such as olive oil. While these results did not prove any particular molecular target, the results were often interpreted to indicate the lipid membrane as the site of anesthetic action (the Meyer-Overton ‘lipoid’ hypothesis), described as follows by Meyer: The narcotizing substance enters in a loose physico-chemical combination with the vitally important lipoids of the cell, perhaps with the lecithin, and in so doing changes their normal relationship to the other cell constituents, through which an inhibition of the entire cell chemism results.1 Although Meyer and Overton recognized limitations to their experimental observations, their work was taken as the basis for a unified ‘lipoid’ theory of anesthesia. The Meyer-Overton theory is not the only unitary theory of anesthesia action. At least seventeen distinct unified theories have been proposed between 1847 and 1997 (see Table 1). It is nearly impossible to find a review article or book chapter on the mechanism of anesthetic action that does not in some way mention the Meyer-Overton hypothesis or a related unified theory of anesthetic action. Table 1 Major Unitary Theories of General Anesthesia Formulated Between 1847 and 1997 While the legacy of Meyer and Overton has dominated investigations of general anesthetics, support for their hypothesis was hardly monolithic. In the last several decades in particular, unified theories of anesthesia have come under increasingly severe attacks and the general,2,3 although by no means unaminous,4–6 consensus is that anesthetics, as with most drugs in current medical use, act at protein receptor targets. A clear symbol of the ‘changing of the guard’ is illustrated by comparing two quotations from the 1990 and 1996 editions of the pharmacology textbook The Pharmacological Basis of Therapeutics. The 1990 edition reads: Most theories of anesthetic action are based on the physicochemical characteristics of the anesthetic drugs. These proposals relate closely to the correlation between the potency of an anesthetic agent and the solubility of the drug in oil…Interpretation of this fundamental result is thought to be crucial to the understanding of the action of anesthetics.7 In the 1996 edition of this text, the above passage was repeated but with the last sentence amended as follows: Interpretation of this fundamental results, once thought to be crucial to the understanding of the action of anesthetics, may be only an incidental finding.8 (italics added) The following sections will focus on three compounds whose actions are inconsistent with the Meyer-Overton hypothesis. Two of the compounds, α-chloralose and chloral hydrate, were anesthetics known to Meyer and Overton, and recognized at least by Overton as having properties which were difficult to explain by his hypothesis. The third compound, flurothyl (hexafluorodiethyl ether) is a volatile, fluorinated ether with convulsant properties which was discovered in 1957. While these three compounds posed a challenge for the Meyer-Overton hypothesis, their properties were mostly ignored by those favoring a unitary theory of anesthesia. The end of this manuscript will speculate on reasons for this.