ABSTRACT
In this contribution, we review the computer simulation studies, reported in the past one and half decades, of lipid membranes in the presence of general anesthetics. Their results are discussed in detail in the frame of the lipid theories, i.e., under the assumption that general anesthesia is caused by certain, anesthetic-induced changes in the properties of the lipid membrane. Taking into account the large chemical variety of the general anesthetics, the fact that several molecules that are chemically rather similar to certain anesthetics have no anesthetic effect, and also pressure reversal, i.e., the vanishing of the anesthetic effect at elevated pressures, the relevant membrane properties must be such that they (i) change in the same way when adding any general anesthetic to the membrane, (ii) do not change this way when adding a non-anesthetic compound to the membrane, even if its structure is rather similar to some anesthetics, and (iii) change the opposite way when increasing the pressure. The review focuses on the distribution of the anesthetic molecules along the membrane normal, the change of various membrane properties upon addition of anesthetics, the differences of the effect of chemically similar anesthetics and non-anesthetics on the various membrane properties, and the phenomenon of pressure reversal. The growing body of results seems to converge to a certain consensus in several respects. The most likely picture that starts emerging from these results in respect of the molecular mechanism of anesthesia is the following. Anesthetic molecules prefer two distinct positions along the membrane normal axis, one close to the headgroup region, and another one in the middle of the bilayer. Anesthesia seems to be caused by the molecules that are in the former preferred position, as they laterally push the lipid molecules farther apart from each other, resulting in a decreased lateral density of the membrane. The additional space created this way allows an increased mobility of the lipid molecules, increasing thus the fluidity of the membrane, and decreases the lateral pressure in the region close to the outer preferred position of the anesthetics. This alteration of the lateral pressure profile affects the conformational equilibrium of certain membrane-bound proteins, which leads then to narcosis.
