Genetics and the Mechanisms of Action of Inhaled Anesthetics

Abstract

Inhaled anesthetics have been used for more than a century, and they are currently administered to millions of patients each year. Although well understood in an empirical sense, their basic molecular mechanisms of action are still unknown. During the past two decades, a large amount of evidence has been presented that is most consistent with the hypothesis that inhaled anesthetics act at multiple sites. For example, genetic mutations exist that distinguish between different inhaled anesthetics, i.e. the mutations alter sensitivity to some anesthetics differently than others. Since it is probable that multiple mechanisms contribute to inhaled anesthetic action, a genetic approach is a powerful method for sorting out which molecules are involved in specific anesthetic effects. This review describes recent pharmacogenetic studies performed using model organisms, including yeast, nematodes, fruit flies, and mice. At first glance, the results of these studies are notable for their lack of a common putative molecular target. In fact, the results suggest that anesthetics interact with a seemingly broad range of cellular components including ion channels, membrane receptors, lipid rafts, and the mitochondrial electron transport chain. However, a unifying theme is beginning to emerge, one that implicates the presynaptic neuron as a common functional target for inhaled anesthetics. Intriguing similarities among the results suggest that many of the findings obtained in model organisms can be generalized across disparate phyla, and that the findings will be applicable in humans. By continuing to exploit the power of genetics, such studies are likely to unravel the great mystery of how inhaled anesthetics produce their effects.

Intraspecific genetic variation for anesthesia success in a New Zealand freshwater snail

“…This observation led us to hypothesize that this lineage effect points to an important role of genetic background in anesthesia success in these snails. This hypothesis finds indirect support from reports of genetically based differences in anesthesia efficacy in rodents (e.g., Chesler et al 2003;Moghil et al 2005;Seltzer 2014), insects (e.g., Guan et al 2000), and roundworms (Morgan and Sedensky 1994;Hawasli et al 2004;reviewed in Nash 2002;Steele et al 2007).…”

Prediction of Toxicity, Sensory Responses and Biological Responses with the Abraham Model

“…However, even if the actual site of action is not known, it is possible that a general mechanism on the lines shown in Figure 4 obtains. In the first stage the anesthetic is transported from the gas phase to a site of action, and in the second stage interaction takes place with a target receptor, a variety of which have been suggested ( (Franks, 2006;Zhang et al, 2007;Steele et al, 2007). Then if stage 1 is a major component, we might expect that a QSAR could be constructed for inhalation anesthesia.…”

Intraspecific genetic variation for anesthesia success in a New Zealand freshwater snail

“…This observation led us to hypothesize that this lineage effect points to an important role of genetic background in anesthesia success in these snails. This hypothesis finds indirect support from reports of genetically based differences in anesthesia efficacy in rodents (e.g., Chesler et al 2003;Moghil et al 2005; Seltzer 2014), insects (e.g., Guan et al 2000), and roundworms (Morgan and Sedensky 1994;Hawasli et al 2004;reviewed in Nash 2002;Steele et al 2007).…”