PHYSICOCHEMICAL NATURE OF THE SITE OF ANESTHETIC ACTION

The preceding sections suggest that anesthetics may act at several gross (e.g., spinal cord versus reticular activating system) or microscopic (e.g., presynaptic versus postsynaptic) sites. The varied nature of these sites, however, does not preclude a unique action at a molecular level. For instance, depression of presynaptic neurotransmitter release and blockade of current flow through the postsynaptic membrane may arise from an anesthetic perturbation at an identical molecular site, even though the geographic locations of these sites differ. The concept that all inhaled anesthetics have a common mode of action on a specific molecular structure is called the unitary theory of narcosis. The nature of this presumed common site has been explored by correlating the physical properties of anesthetics with their potencies. The rationale behind this approach is that the best correlation between anesthetic potency and a physical property suggests the nature of the anesthetic site of action. For example, the correlation of MAC and lipid solubility implies that the site of action is hydrophobic. The correlations that depend on forces exerted between anesthetic molecules (e.g., the boiling point of an anesthetic) are not important to the study of anesthetic mechanisms; as such, intermolecular forces cannot be representative of a single site of action. These correlations are defined by the interaction of each anesthetic with itself rather than with a common site.

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Hydrophobic Site: The Meyer-Overton Rule

The physical property that correlates best with anesthetic potency is lipid solubility ( Table 4-2 and Fig. 4-9 ).^{[87] [88] [89]} This correlation is called the Meyer-Overton rule, after its two discoverers. For most inhaled agents, the product of the anesthetizing partial pressure and its olive oil-gas partition coefficient varies little over approximately a 100,000-fold range of anesthetizing partial pressures (see Table 4-2 and Fig. 4-9 ). For the correlation to be perfect, this product would have to be the same for all anesthetics for a given animal. Within a given species, an even better correlation between anesthetic potency and solubility may be obtained with solvents that are better characterized than olive oil, such as lecithin, an amphipathic phospholipid with hydrophobic and polar components.^[90] The closeness of this correlation implies a unitary molecular site of action and suggests that anesthesia results when a specific number of anesthetic molecules occupy a crucial hydrophobic region in the CNS. This finding has led many investigators to look for the molecular basis of anesthetic action in cellular hydrophobic regions.

Figure 4-9 Correlation of the minimum alveolar concentration (MAC) in humans and dogs and the righting-reflex 50% effective dose (ED₅₀ ) in mice with lipid solubility (i.e., the olive oil-gas partition coefficient). Values are taken from Table 4-2 .