Explaining general anesthesia: a two-step hypothesis linking sleep circuits and the synaptic release machinery

Bioessays. 2014 Apr;36(4):372-81. doi: 10.1002/bies.201300154. Epub 2014 Jan 22.


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.

Keywords: Caenorhabditis elegans; Drosophila; SNARE; general anesthesia; neuroscience; sleep; syntaxin.

MeSH terms

  • Anesthesia, General*
  • Anesthetics, General / pharmacology*
  • Animals
  • Disease Models, Animal
  • Drosophila / physiology
  • Humans
  • Rodentia
  • SNARE Proteins / metabolism*
  • Sleep / drug effects*
  • Sleep / physiology*
  • Synapses / drug effects*
  • Synapses / physiology
  • Syntaxin 1 / metabolism*
  • Unconsciousness


  • Anesthetics, General
  • SNARE Proteins
  • Syntaxin 1