Since its introduction in the 1840s, general anesthesia has transformed medicine, yet its mechanisms—particularly lipid-associated effects—remain unclear. Meyer (1899) and Overton (1901) demonstrated that anesthetic potency is directly correlated to hydrocarbon solubility. This long-established principle, known as the Meyer-Overton correlation, implies a key underlying role of the lipid bilayer in mediating general anesthetic action. Cellular exocytosis is a critical lipid-based physiological process. Accordingly, to assess anesthetic effects on liposome fusion, we use a protein-free membrane model. Our prior work showed that short-chain alcohols modulate fusion, with extracellular ethanol decreasing rates by 29% at the US legal intoxication level of 0.08% w/v (Paxman et al., 2017, Biophy. J, 112:121-132). This likely contributes to the depressant effects of drinking alcohol. We hypothesize that inhalable general anesthetics alter vesicle fusion similarly. To test this, we are examining three agents spanning potencies predicted by the Meyer-Overton correlation: ethanol, diethyl ether, and chloroform. Clinically relevant doses are delivered as vapor, quantified by gas chromatography, and fusion rates are recorded. Consistent with our prior findings, ethanol vapor shows inhibition of liposome fusion. Ether produced similar inhibition at lower doses, congruous with its greater lipid solubility. These data are consistent with ethanol and ether directly inhibiting vesicle fusion, by increasing the activation energy of fusing membranes. If so, we would expect general anesthetics to reduce synaptic vesicle fusion with neuronal membranes in vivo. The resultant decrease in neurotransmitter release would combine with any anesthetic effects exerted upon membrane proteins. These findings may inform anesthetic protocol refinement, enhance procedural safety, and contribute to advancement of neuroscientific knowledge and medical care worldwide.
Poland et al. (Sun,) studied this question.