Physical Aspects of the Cut-Off Effect of N-Alcohols in Pure Lipid Membranes

Abstract

Nowadays, the molecular nature of general anesthetic target sites remains unknown; some theories profess that the action occurs in proteins, others in lipids. In particular, for nearly a century it has been known that alcohols can act as general anesthetics. However, as the chain length of an alcohol increases, so does its potency as an anesthetic, only up to a certain chain length beyond which the anesthetic activity disappears (the so-called effect). In the attempt to explain such phenomenon, and based on the proposed anesthetic theories, different explanations have emerged without conclusive arguments, nevertheless, the lack of sufficient evidences supporting the cut-off effect of n-alcohols in general anesthesia make this work worth to be pursue. In the present work, using calorimetry and atomic force microscopy (AFM), we show a systematic study of the interaction of n-alcohols (from methanol, C1, to eicosanol, C20) with lipid membranes, in order to collaborate in the comprehension of a physical mechanism of the cut-off phenomenon. Our results suggest that the lowering of the melting transition temperature (Tm) of lipid membranes due to short-chain alcohols, is highly related to their ability to disturb lipid membranes (as has been shown for a wide variety of anesthetics), whilst, the increase of Tm induced by long-chain ones (from C12), is caused by a stiffening of the lipid membrane. We also correlate such effects with some physical properties of n-alcohols and the lipid composition. These results concur with other findings to underwrite the idea that anesthesia does not need a specific binding site in a protein and allow us to speculate that anesthesia only depends on the ability of certain atom or molecule to solubilized in lipids increasing the disorder of the membrane.