Theories of General Anaesthetic Action - Outdated Lipid Hypotheses of General Anaesthetic Action

Outdated Lipid Hypotheses of General Anaesthetic Action

From the correlation between lipid solubility and anaesthetic potency, both Meyer and Overton had surmised a unitary mechanism of general anaesthesia. They assumed that solubilization of lipophilic general anaesthetic in lipid bilayer of the neuron causes its malfunction and anaesthetic effect when critical concentration of anaesthetic is reached. Later in 1973 Miller and Smith suggested the critical volume hypothesis also called lipid bilayer expansion hypothesis. They assumed that bulky and hydrophobic anaesthetic molecules accumulate inside the hydrophobic (or lipophilic) regions of neuronal lipid membrane causing its distortion and expansion (thickening) due to volume displacement. Accumulation of critical amounts of anaesthetic causes membrane thickening sufficient to reversibly alter function of membrane ion channels thus providing anaesthetic effect. Actual chemical structure of the anaesthetic agent per se is not important, but its molecular volume plays the major role: the more space within membrane is occupied by anaesthetic - the greater is the anaesthetic effect. Based on this theory, in 1954 Mullins suggested that the Meyer-Overton correlation with potency can be improved if molecular volumes of anaesthetic molecules are taken into account. This theory existed for over 60 years and was supported by experimental fact that increases in atmospheric pressure reverse anaesthetic effect (pressure reversal effect).

Then other theories of anaesthetic action emerged mostly ‘physicochemical’ theories that took into account the diverse chemical nature of general anaesthetics and suggested that anaesthetic effect is exerted through some perturbation of the lipid bilayer. Several types of bilayer perturbations were proposed to cause anaesthetic effect (reviews):

• changes in phase separation
• changes in bilayer thickness
• changes in order parameters
• changes in curvature elasticity

According to the lateral phase separation theory anaesthetics exert their action by fluidizing nerve membranes to a point when phase separations in the critical lipid regions disappear. This anaesthetic-induced fluidization makes membranes less able to facilitate the conformational changes in proteins that may be the basis for such membrane events as ion gating, synaptic transmitter release, and transmitter binding to receptors.

All these outdated lipid theories generally suffer from four weaknesses (full description see in sections below):

• Stereoisomers of an anaesthetic drug have very different anaesthetic potency whereas their oil/gas partition coefficients are similar
• Certain highly lipid soluble drugs expected to act as anaesthetics, exert convulsive effect instead of anaesthetic effect and therefore such drugs were termed nonimmobilizers.
• General anaesthetic-induced changes in membrane density and fluidity are so small that relatively small increases in temperature can mimic these effects on membrane fluidity and density without causing anaesthesia.
• Cutoff effect - addition of methylene groups to a homologous series of long chain alcohols, or alkanes, increases their lipid solubility and should thereby produce a corresponding increase in anaesthetic potency, but it was observed only to a certain "cutoff" length of the chain.

In conclusion it is important to point out that the correlation between lipid solubility and potency of general anaesthetics is a necessary but not sufficient condition for inferring a lipid target site. General anaesthetics could equally well be binding to hydrophobic target sites on proteins in the brain. The main reason that more polar general anaesthetics are less potent is that they have to cross the blood–brain barrier to exert their effect on neurons in the brain.