Lipid-mediated Action of Local Anesthetics on Ion Channels in Membranes

Abstract

In general, anesthetic action is different from other drug effects on three points, its non-specific aspect, its very high dose compared to other drugs, and the reversibility of the effect. Most small non-polar molecules show anesthetic effect, however, a rather limited number of them are clinically used because of the cost, other toxic effect, and practical factors. From the above physico-chemical aspect of anesthetic, the lipid biomembrane has been considered to play a crucial role irrespective of receptors or specific binding enzymes. For instance, it is well known that the required minimum anesthetic concentration in terms of the mole fraction of anesthetics is inversely proportional to its partition coefficient, S, between the bulk aqueous solution and membrane. This fact strongly suggests that the change of the membrane due to the enrichment of anesthetics indirectly causes the anesthetic action. It is our aim to propose a simple molecular model of this effect, which will allow us to take into account some natures of the molecular structure of both the anesthetic and the lipid bilayer matrix. Since anesthetics are amphiphilic molecules they concentrate at the interface between polar head group region and lipophilic region. Cantor evaluated the effect of anesthetics to the change of the lateral pressure profile in the perpendicular direction of the lipid membrane surface. By this indirect effect, he showed that anesthetics could modulate the equilibrium of membrane proteins. Although his idea of modulation in the pressure profile of membrane by additive molecules is appreciated, the validity of the assumed force field exerted on head and chain parts of a lipid molecule is not warranted. Instead of employing a tedious procedure for calculating pressure profile, we shall look for a pressure change in a particular region rather than for a change of an overall pressure profile along a bilayer depth. To start with, we assume the following. An increase of the cross section of an ion channel in a polar head group region during its transition from closed to open state,