Genetic Effects inDrosophilaon the Potency of Diverse General Anesthetics: A Distinctive Pattern of Altered Sensitivity

Abstract

Mutations that influence the sensitivity of an organism to a volatile general anesthetic can be divided into two classes. In one, sensitivity to all other volatile agents is affected to a similar degree. Although this class may contain mutations of interest for understanding anesthesia, it is also likely to contain mutations that merely alter general health. In the second class, mutations confer non-uniform effects on potency (NEP), i.e., larger effects for some volatile anesthetics than for others. Members of this class are of special interest for studies of arousal and its pharmacological suppression because they not only avoid the pitfall of effects on global health, they imply the existence of drug targets that are preferentially affected by particular agents. In this work we provide the first systematic investigation of the relative frequency and diversity of NEP mutations in Drosophila. As a first step we isolated and characterized a set of P element insertion mutations that confer altered sensitivity of the fruit fly to the clinical anesthetic halothane. Then we tested the members of this collection for their effect on the sensitivity of flies to five other volatile agents. Not only do we find that most of the mutations show non-uniform effects, they share a characteristic arrangement of altered potencies (halothane >>desflurane ≥ enflurane ∼ isoflurane ∼ methoxyflurane > sevoflurane). From this result, although we do not know how direct or indirect are the effects of the mutations, we infer the existence of a biologically relevant target for anesthetic action that has a distinct preference for halothane over other agents. Intriguingly, P element insertions that co-map with several NEP loci have been shown to alter the fly's response to cocaine and ethanol, suggesting that common genetic elements are involved in the response to all three drugs.

Rapid Eye Movement Sleep Debt Accrues in Mice Exposed to Volatile Anesthetics

“…It has become increasingly clear that many agent-specific differences exist amongst anesthetics, including diversity in the neuronal mechanisms through which individual drugs produce the anesthetic state. 23,29–34 …”

Drosophila Ryanodine Receptors Mediate General Anesthesia by Halothane

“…Previous work identified target genes for anesthetic action that have a distinct preference for halothane over other anesthetic agents, implying the presence of agent-specific pathways 2,8 . To determine the level of anesthetic specificity of dRyr, we assayed the responses of dRyr mutants to sevoflurane, enflurane, and isoflurane, and compared them to the response to halothane using a two-way ANOVA (Generalized Linear Model; Figure 1D).…”

“…First, voltage-insensitive (“leak”) ion channels, which act to hyperpolarize neurons, have repeatedly appeared in genetic screens for targets of volatiles 2,3,5,7 suggesting that they act, at least in part, through changes in voltage and resistance across the plasma membrane. Second, the response to each anesthetic compound is affected differently by a given mutant, suggesting the presence of agent-specific pathways 2,8 . Finally, mutations in these genes reduce, but do not eliminate sensitivity to volatile anesthetics, indicating that additional anesthetic targets remain unidentified.…”

Metabolomics and Whole-Exome Sequencing in Patients with Differential Sensitivity to Sevoflurane: A Protocol for a Prospective Observational Trial

“…Mutations of several genes are associated with altered sensitivity to volatile anesthetics in fruit flies, nematodes and mice ( Campbell et al, 2009 ; Nagasaka et al, 2017 ; Awal et al, 2020 ). The product of Gas-1 gene is a subunit of mitochondrial complex I ( Kayser et al, 2004 ).…”