Abstract
The molecular mechanism of general anesthesia is still a controversial issue. Direct effect by linking of anesthetics to proteins and indirect action on the lipid membrane properties are the two hypotheses in conflict. Atomistic simulations of different lipid membranes subjected to the effect of small volatile organohalogen compounds are used to explore plausible lipid-mediated mechanisms. Simulations of homogeneous membranes reveal that electrostatic potential and lateral pressure transversal profiles are affected differently by chloroform (anesthetic) and carbon tetrachloride (non-anesthetic). Simulations of structured membranes that combine ordered and disordered regions show that chloroform molecules accumulate preferentially in highly disordered lipid domains, suggesting that the combination of both lateral and transversal partitioning of chloroform in the cell membrane could be responsible of its anesthetic action.
Highlights
The effect of chloroform (CHCL3) on lipid bilayers has been extensively studied during the past decades, in part motivated by the desire to understand its toxicity in cells [1]
Molecular Dynamic (MD) simulations have unveiled the molecular mechanism that explains this differential behavior: due to its particular interaction with cholesterol, chloroform induces a strong chain disordering in liquid-ordered membrane phases containing cholesterol, whereas it promotes chain ordering in liquiddisordered membrane phases with low cholesterol contents [6]
The main drawback of the lipid-mediated mechanisms is that most the experiments that analyze the effects of anesthetic compounds on model lipid bilayers have been made at anesthetic concentrations much higher than those clinically required to promote block nerve conduction
Summary
The effect of chloroform (CHCL3) on lipid bilayers has been extensively studied during the past decades, in part motivated by the desire to understand its toxicity in cells [1]. The diversity of molecular structures of anesthetic compounds and the wide variety of responding systems are difficult to reconcile with the specific binding concept and suggested an alternative hypothesis based on a nonespecific mechanism through an alteration of the global physical properties of the membrane lipid matrix (thickness, area, chain ordering, melting temperature) [10,11,12,13]. This hypothesis is supported by the Meyer-Overton’s rule that correlates the potency of anesthetic drugs with how well they dissolve in olive oil. At pharmacological concentrations, little effects on the global properties of synthetic membranes are observed [14]
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