Pressure-induced exclusion of a local anesthetic from model and nerve membranes

Because it is well established that the anesthetic state can be reversed by pressure, a number of molecular theories that have been proposed for the mechanism of action of both local and general anesthetics can be tested by varying the pressure. Using Fourier transform infrared spectroscopy, we report here the first direct observation of the expulsion from lipid bilayers of a local anesthetic, tetracaine, by pressure. Moreover, we establish for the first time that this phenomenon is common to both model membranes and to myelinated and unmyelinated nerve membranes, vindicating the utility of model membrane systems. A distinctive feature of this behavior in model systems is that, in saturated phosphatidylcholines at high pH, expulsion only occurs in the presence of cholesterol, whose ordering effect on the acyl chains evidently assists pressure in squeezing the anesthetic out of the bilayer. This pressure-induced phenomenon may provide insight into the molecular mechanisms underlying the antagonistic effect of pressure against anesthesia.