Anesthesia from Physical Interactions with Lipophilic Membrane Components

The idea that a physical interaction is important stems from experimental observations made in the late nineteenth and early twentieth centuries, when it was recognized that noble gases such as xenon, which do not chemically interact with tissues, produce unconsciousness. Also, anesthesia produced at ambient atmospheric pressure can be attenuated by physically raising the pressure to 100 atm, a phenomenon known as pressure reversal. Finally, a clear correlation exists between anesthetic potency and the physical parameter lipid solubility, suggesting that anesthesia may be produced when anesthetics physically dissolve into the cell membrane's lipid biophase (Meyer Overton rule). Such a correlation is shown in Fig. 25.6, where anesthetic potency is expressed as MAC and lipid solubility is estimated as the oil-gas partition.

Membrane conformational changes are observed on exposure to anesthetics, further supporting the importance of physical interactions that lead to perturbation of membrane macromolecules. For example, exposure of membranes to clinically relevant concentrations of anesthetics causes membranes to expand beyond a critical volume (critical volume hypothesis) associated with normal cellular function. Additionally, membrane structure becomes disorganized, so that the insertion of anesthetic molecules into the lipid membrane causes an increase in the mobility of the fatty acid chains in the phospholipid bilayer (membrane fluidization theory) or prevent the interconversion of membrane lipids from a gel to a liquid form, a process that is assumed necessary for normal neuronal function (lateral phase separation hypothesis).

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