Explaining general anesthesia: A two‐step hypothesis linking sleep circuits and the synaptic release machinery

Abstract

Several general anesthetics produce their sedative effect by activating endogenous sleep pathways. We propose that general anesthesia is a two-step process targeting sleep circuits at low doses, and synaptic release mechanisms across the entire brain at the higher doses required for surgery. Our hypothesis synthesizes data from a variety of model systems, some which require sleep (e.g. rodents and adult flies) and others that probably do not sleep (e.g. adult nematodes and cultured cell lines). Non-sleeping systems can be made insensitive (or hypersensitive) to some anesthetics by modifying a single pre-synaptic protein, syntaxin1A. This suggests that the synaptic release machinery, centered on the highly conserved SNARE complex, is an important target of general anesthetics in all animals. A careful consideration of SNARE architecture uncovers a potential mechanism for general anesthesia, which may be the primary target in animals that do not sleep, but a secondary target in animals that sleep.

What is unconsciousness in a fly or a worm? A review of general anesthesia in different animal models

“…However, the initial entry into the behaviorally anesthetized state seems to require activation of endogenous sleep mechanisms for humans, rodents and flies. The likely absence of a sleep circuit in adult worms exposes a second, conserved target of general anesthetics: the synaptic release machinery, and more specifically, the syntaxin1A protein ( van Swinderen & Kottler, 2014). Thus, effects on synaptic release across the brain result in altered patterns of activity that prevent behavioral responsiveness.…”

“…This indicates that there is a connection between sleep and general anesthesia in mammals and flies, yet it is clear that sleep pathways are not the sole mechanism for general anesthesia. Rather, there is an emerging view that the sedative component of general anesthesia is mediated through sleep pathways (Franks, 2008;Nelson et al, 2002;van Swinderen & Kottler, 2014).…”

“…For C. elegans, it is therefore unlikely that general anesthetics activate an endogenous sleep pathway, whereas evidence suggests this occurs for rodents and even flies. Therefore, loss of consciousness in humans, LORR in mice, and loss of responsiveness to startle in flies, which all occur at relatively low drug concentrations (e.g., 0.3-0.7 vol% isoflurane), are likely to be behavioral manifestations of the activation of a sleep pathway by general anesthetics ( van Swinderen & Kottler, 2014). Since adult worms probably lack a sleep pathway, this potentially explains why the behavioral complexity thesis is most prominent in worms, as it is not masked by any sleep-related anesthetic effects.…”

Behavioral and electrophysiological analysis of general anesthesia in 3 background strains ofDrosophila melanogaster

“…Larvae have a different nervous system to the adult fly, 18,19 thus a thorough investigation of general anesthesia in Drosophila should ideally examine both life stages, due to these distinct brain architectures found in both animals. Importantly, it is unclear whether fly larvae sleep, 20 so if the isoflurane resistance effects seen in w 1118 stem from sleep-related processes, 10 then these might not manifest in a life stage that may not have yet developed the relevant sleep circuitry. On the other hand, isoflurane resistance in w 1118 larvae might suggest a more systemic effect.…”

“…6,21,22 Isoflurane decreases transmitter release at the NMJ We have recently proposed an alternative mechanism for general anesthesia that involves the synaptic release machinery. 14,20 To investigate if the decreases in larval coordination under general anesthesia reflected a change in neurotransmitter release, synaptic transmission was examined at the larval neuromuscular junction (NMJ) (Fig. 4A).…”