answer:I hope you get a comprehensive answer to this. Sounds fascinating. I’m not sure if this will help, however it might be worth looking at. More than 100 years ago. Ham Meyer in Marburg (1) and Charles Ernest Overton in Zurich (2) independently found that the action of general anesthetics is related to their partition coefficient between water and olive oil. Overton performed experiments on tadpoles and recorded the critical drug concentration, ED^sub 50^, at which they stopped swimming. Assuming that the solubility of these anesthetics in olive oil is proportional to that in biomembranes, he suggested that this critical concentration corresponded to a fixed concentration in biomembranes. The Meyer-Overton rule can be expressed as [ED^sub 50^] × P [equal] const, where P is the partition coefficient of the anesthetic drug between membranes and water. Small molecules, as different as nitrous oxide, chloroform, octanol, diethylether, procaine, and even the noble gas xenon, all act as anesthetics. Overton noted that this action is completely unspecific, i.e., dependent only on the solubility of the anesthetic in oil and independent of its chemical nature. Surprisingly, this finding is still valid for general and local anesthetics (2–5) but remains unexplained. Overton concluded that this nonspecific! Iy requires a single mechanism based on physical chemistry and not on the molecular structure of the drugs. Although the close relation between anesthetic effect and solubility in lipids led many scientists to believe that anesthetic action is lipid-related, no model was proposed by Meyer and Overton or by later research. It is known, however, that lipid-melting transitions are lowered in the presence of anesthetics. This has been related to the anesthetic function (6,7). In the absence of a satisfactory physiological membrane mechanism, many others prefer to view the action of anesthetics as due to specific effects on proteins, e.g., sodium channels or luciferase (8–10). Since anesthetics act on nerves and the Hodgkin-Huxley theory for the action potential is based on the opening and closing of ion channels, it seems natural to attribute the action of anesthetics to interactions with these channels. Some anesthetics show a stereospecificity indicating that the effective anesthetic concentration (ED^sub 50^) is different for the two chiral forms even though the partition coefficient is not affected to the same degree ( 11 ). In this regard, however, we note that lipid molecules are also chiral. While it is widely believed that local anesthetics are sodium channel blockers, a satisfactory general model of how anesthetics act on proteins is again lacking. The action of anesthetics is still mysterious. Some lipid and protein theories on anesthesia are reviewed in the literature (8,12). The general absence of specificity and the strong correlation between solubility in lipid membranes and anesthetic action seems to speak against specific binding and a protein mechanism. On the other hand, there is clear evidence that the action of some proteins is influenced by anesthetics. Data on the influence of anesthetics on luciferase and on Na- and K-channels are summarized in Firestone et al. (13) and suggest that the action of lipids and that of proteins are coupled in some simple manner. Cantor has thus proposed that all membrane-soluble substances alter the lateral pressure in the hydrocarbon region and thereby influence the structure of proteins (14–16). Lee proposed a coupling of protein function to the transition temperature of a lipid annulus at the protein interface ( 17). While such mechanisms may provide a control of protein function, it is nevertheless remarkable that all animals are affected to the same degree by anesthetics, suggesting that anesthetic action is largely independent of the specific protein composition of membranes. (see (2), foreword to the English edition.) In addition to their effect on nerves, anesthetics also change membrane properties such as permeability and/or the hemolysis of erythrocytes (5,13). This indicates the need for a more general view of anesthetic action. In this article, we focus on a thermodynamic description of general anesthesia based on lipid properties. We recognize that this can seem heretical given the dominance of the ion channel picture. Nevertheless, there are a variety of reasons for considering a macroscopic thermodynamic view. The striking fact that noble gases can act as general anesthetics speaks against specific binding to macromolecules. In particular, the Meyer-Overton rule would require all anesthetics to have exactly the same partition coefficient between lipid membrane and protein binding sites for all relevant proteins. It is difficult to imagine that nature provides binding sites for such a variety of molecules on the same protein in precisely such a manner that binding affinity is independent of chemical nature. (It is unlikely that one protein provides binding sites for all anesthetics. Therefore, if a protein picture was to be maintained one has to abandon a unique mechanism for anesthesia (Keith Miller, Harvard Medical School, private communication, 2006.)) An acceptable description should account for this evident lack of specificity, and this suggests the utility of thermodynamic arguments. Moreover, it is to be emphasized that thermodynamics is not inimical to microscopic (e.g., ion-channel) descriptions of the same phenomena. No one would claim, for example, that the manifest successes of thermodynamics in describing the properties of real gases in any way contradict the tact that they are composed of interacting atoms. Thermodynamics rather recognizes that many macroscopic phenomena are independent of such microscopic details and that a large number of microscopic systems can display features, which are bolh qualitatively and quantitatively susceptible to more generic methods. Precisely the absence of detail means that thermodynamic approaches are often capable of making testable quantitative predictions, which are often inaccessible to or obscured by more microscopic models. Thus, we wish to propose a simple thermodynamic explanation of the MeyerOverton rule based on the well-known physical chemical phenomenon of freezing-point depression. We will show that this picture has the benefit of providing an immediate and intuitive picture for the pressure reversal of anesthesia as a consequence of the pressure-induced elevation of the melting point in lipid membranes and can explain the effects of inflammation and divalent cations on anesthetic action. source: The Biophysical Journal; Thermodynamics of General Anesthesia.
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