IGN is thought to be produced by the same mechanism as general anaesthesia with gases or volatile liquids. The inert gases and most volatile anaesthetic agents are simple molecules with no common structural feature, and they do not undergo chemical change in the body to exert their effect. This property suggests that a physical rather than chemical effect must be involved, and most research is based on the hypothesis that the mechanism is the same for all agents (the unitary hypothesis of narcosis). For this reason, the considerable efforts to understand the mechanism of action for anaesthetic agents are thought to have direct relevance for IGN.
At the turn of the twentieth century, Meyer and Overton noted a strong correlation between the lipid solubility of an anaesthetic agent and its narcotic potency, and this relationship has become known as the Meyer-Overton Hypothesis. Later, in 1923, Meyer and Hopf stated ‘all gaseous and volatile substances induce narcosis if they penetrate cell lipids in a definite molar concentration which is characteristic for each type of cell and is approximately the same for all narcotics’. This means that the higher the oil-water partition coefficient (relative solubility) the more potent the inert gas. The hypothesis is that inert gas molecules are dissolved in the lipid membranes of neurons and somehow interfere with cell membrane function so that the higher the proportion of an agent dissolved in lipid, the more potent the agent as a narcotic (anaesthetic). In truth, it has long been realized there is more to anaesthetic action than this because there are some discrepancies in this relationship (Figure 15.2). For example, although both neon and hydrogen have been shown to be narcotic, neon appears to be more so despite a similar oil-water partition coefficient, and argon is about twice as narcotic as nitrogen but again has a similar oil-water solubility ratio. There are also anomalies among the volatile anaesthetics agents, but, in general, the relationship is much closer than with other physical properties. Intravenous general anaesthetic agents (e.g. thiopentone and propofol) do not fit this relationship and almost certainly produce narcosis through a different mechanism.
The lipid solubility hypothesis has been extended by the critical volume concept10. Here, the consequence of the narcotic agent dissolved in the lipid membrane is proposed to cause swelling of the membrane. At a critical volume, the swollen membrane somehow produces the clinical features of anaesthesia. Thus, there is a lipid volume change that differentiates the anaesthetized from the unanaesthetized state. Other factors, in particular pressure compressibility of the lipid, also affect volume. That some narcotic effects can be reversed by application of increased hydrostatic pressure lends weight to this hypothesis. (See also Chapter 20, on the high pressure neurological syndrome [HPNS]).
Exceptions in both animal and human studies have led to a further refinement – the multi-site expansion model11. This model postulates that expansion occurs variably at more than one molecular site and that pressure does not act equally at the same sites. Thus, hydrostatic pressure effects (see Chapter 20) or narcotic effects may predominate.
The physical theories, in general, support the concept that the site of action is a hydrophobic portion of the cell, the traditional view being that this is the cell membrane. Many studies show that membranes are resistant to the effects of anaesthetics, and other sites have been sought, such as the hydrophobic regions of proteins or lipoproteins. More recent studies have suggested that the site of action is a protein, rather than a lipid, and that narcotics act by competitive binding to specific receptors, thus affecting synaptic transmission. It has even been postulated that although impairment of cognitive function is a result of the inert gas narcotic effect, impaired motor ability is a consequence of raised hydrostatic pressure per se12. Not all experimental observations are easily reconciled, and the definitive description of the mechanism of action for volatile anaesthetic agents at the molecular level remains to be elucidated. For those interested in delving deeper into this area, see Pleuvry.
The site of action is most likely at a synaptic level, and many studies have looked at inhibitory and excitatory neurotransmitters and receptors in the central nervous system. Neurotransmitters studied include noradrenaline (norepinephrine), serotonin, dopamine, gamma-aminobutyric acid (GABA) and glycine. GABA is the most important inhibitory transmitter in the brain. Potentiation of inhibitory pathway synapse receptors (GABA receptors) is suspected to be a major component of IGN/anaesthesia, although action at a wide variety of neuronal sites is likely.
Exposure to narcosis raises extracellular dopamine in the area of the brain controlling the extrapyramidal system, at least in rats. This action may account for some of the neuromuscular disturbances of IGN. In contrast, dopamine is increased when HPNS is exhibited (see Chapter 20).