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Cited by 151Anesthesia and Sedative AgentsAnesthesia and Neurotoxicity ResearchNeuroscience and Neuropharmacology Research

The Biology of General Anesthesia from Paramecium to Primate

Open access
Kelz, Max B., Mashour, George A.·2019·Current Biology
DOI 10.1016/j.cub.2019.09.071PMC PMC6902878
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Abstract

General anesthesia serves a critically important function in the clinical care of human patients. However, the anesthetized state has foundational implications for biology because anesthetic drugs are effective in organisms ranging from paramecia, to plants, to primates. Although unconsciousness is typically considered the cardinal feature of general anesthesia, this endpoint is only strictly applicable to a select subset of organisms that are susceptible to being anesthetized. We review the behavioral endpoints of general anesthetics across species and propose the isolation of an organism from its environment - both in terms of the afferent arm of sensation and the efferent arm of action - as a generalizable definition. We also consider the various targets and putative mechanisms of general anesthetics across biology and identify key substrates that are conserved, including cytoskeletal elements, ion channels, mitochondria, and functionally coupled electrical or neural activity. We conclude with a unifying framework related to network function and suggest that general anesthetics - from single cells to complex brains - create inefficiency and enhance modularity, leading to the dissociation of functions both within an organism and between the organism and its surroundings. Collectively, we demonstrate that general anesthesia is not restricted to the domain of modern medicine but has broad biological relevance with wide-ranging implications for a diverse array of species.

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Crossref · 10.1016/j.cub.2019.09.071

Cites

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Claims the paper makes

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  • Premisenone given
    § The Biology of General Anesthesia from Paramecium to Primate

    Organisms from bacteria to plants and humans show similar functional disruption over a narrow tenfold volatile anesthetic concentration range.

    “From bacteria to yeast, from worms to flies, from plants to poets, all of life’s creations show a similar disruption of function within a relatively narrow 10-fold volatile anesthetic range.”
    Quote in the paperSubstantial claim
  • Interpretationcitation
    § The Biology of General Anesthesia from Paramecium to Primate

    Behaviorally quiescent or sleep-like states may be as globally widespread as susceptibility to volatile anesthetics.

    “behaviorally quiescent or sleep-like states may be as globally penetrant as susceptibility to volatile anesthetics [22–29].”
    Quote in the paperSubstantial claim0 of 8 sources checked
    • cites [22] Vorster, 2014, Characterization of sleep in Aplysia californica, Sleep

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    • cites [23] Zhdanova, 2001, Melatonin promotes sleep-like state in zebrafish, Brain Res. source

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    • cites [24] Raizen, 2008, Lethargus is a Caenorhabditis elegans sleep-like state, Nature source

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    • cites [25] Tobler, 1983, Effect of forced locomotion on the rest-activity cycle of the cockroach, Behav. Brain Res. source

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    • cites [26] Omond, 2017, Inactivity is nycthemeral, endogenously generated, homeostatically regulated, and melatonin modulated in a free-living platyhelminth flatworm, Sleep

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    • cites [27] Hendricks, 2000, Rest in Drosophila is a sleep-like state, Neuron source

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    • cites [28] Tu, 2007, The yeast metabolic cycle: insights into the life of a eukaryotic cell, Cold Spring Harb. Symp. Quant. Biol. source

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    • cites [29] Nath, 2017, The jellyfish cassiopea exhibits a sleep-like state, Curr. Biol. source

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  • Premisereasoning
    § The Biology of General Anesthesia from Paramecium to Primate

    No single gene mutation completely removes volatile anesthetic responsiveness.

    “no single gene mutation fully ablates volatile anesthetic responsiveness.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [11] Heurteaux, 2004, TREK-1, a K+ channel involved in neuroprotection and general anesthesia, EMBO J. source

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    • cites [12] Humphrey, 2002, Understanding anesthesia: making genetic sense of the absence of senses, Hum. Mol. Genet. source

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    • cites [13] Petrenko, 2007, Mutation of alpha1G T-type calcium channels in mice does not change anesthetic requirements for loss of the righting reflex and minimum alveolar concentration but delays the onset of anesthetic induction, Anesthesiology source

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    • cites [14] van Swinderen, 1999, A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans, Proc. Natl. Acad. Sci. USA source

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  • Interpretationreasoning
    § The Biology of General Anesthesia from Paramecium to Primate

    Anesthetic responsiveness is pervasive across nature.

    “there is no arguing that anesthetic responsiveness is pervasive across nature.”
    Quote in the paperSubstantial claim
  • Premisenone given
    § The Biology of General Anesthesia from Paramecium to Primate

    Anesthetic drugs act on organisms as diverse as paramecia, plants, and primates.

    “because anesthetic drugs are effective in organisms ranging from paramecia, to plants, to primates”
    Quote in the paperSubstantial claim
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  • Classified as probably not a substantial claim. 8
  • The quote only partly states this claim. 1

  • May combine two claims.

    Premisecitation
    § The Biology of General Anesthesia from Paramecium to Primate

    Mitochondrial energetics, cytoskeletal structure, and ion channel function are essential life features known to be affected by anesthetics.

    “Common features deemed essential for life that are known to be affected by anesthetics include mitochondrial energetics, cytoskeletal structure, as well as ion channel function.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § The Biology of General Anesthesia from Paramecium to Primate

    General anesthesia is not limited to modern medicine and has broad biological relevance across diverse species.

    “Collectively, we demonstrate that general anesthesia is not restricted to the domain of modern medicine but has broad biological relevance with wide-ranging implications for a diverse array of species.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § The Biology of General Anesthesia from Paramecium to Primate

    The proposal that a single conserved anesthetic receptor inherited from a common unicellular ancestor explains evolutionary invariance is doubtful and lacks experimental support.

    “Hence, the reductionist notion that a single, conserved, anesthetic-responsive “receptor,” derived from a common one-celled ancestor, might underlie the observed evolutionary invariance remains dubious and without experimental evidence despite a four decade-long search.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Interpretationcitation
    § The Biology of General Anesthesia from Paramecium to Primate

    Anesthetics occupying sparsely packed lipophilic pockets in proteins are hypothesized to limit conformational flexibility and reversibly impair function.

    “Hence, occupancy of sparsely packed lipophilic pockets is hypothesized to restrict a protein’s conformational flexibility and reversibly impair its function [17, 18].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Eckenhoff, 2008, Why can all of biology be anesthetized?, Anesth. Analg. source

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    • cites [18] Crowder, 2008, Does natural selection explain the universal response of metazoans to volatile anesthetics?, Anesth. Analg. source

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  • May combine two claims.

    Premisecitation
    § The Biology of General Anesthesia from Paramecium to Primate

    Within a species, volatile anesthetic responsiveness varies little; in mice, the most and least sensitive strains differ by less than 40%.

    “For example, in mice the difference between the most and least sensitive strains is less than 40% [10].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Sonner, 1999, Mouse strain modestly influences minimum alveolar anesthetic concentration and convulsivity of inhaled compounds, Anesth. Analg. source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given
    § The Biology of General Anesthesia from Paramecium to Primate

    Unconsciousness is usually regarded as the main feature of general anesthesia, yet that endpoint applies strictly only to some organisms that can be anesthetized.

    “Although unconsciousness is typically considered the cardinal feature of general anesthesia, this endpoint is only strictly applicable to a select subset of organisms that are susceptible to being anesthetized.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning
    § The Biology of General Anesthesia from Paramecium to Primate

    General anesthetics, from single cells to complex brains, produce inefficiency and increase modularity, causing dissociation of functions within an organism and between the organism and its surroundings.

    “we conclude with a unifying framework related to network function and suggest that general anesthetics— from single cells to complex brains—create inefficiency and enhance modularity, leading to the dissociation of functions both within an organism and between the organism and its surroundings.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Anesthetic actions on pLGICs are not limited to GABAA receptors and are not unique to mammals.

    “Anesthetic actions on pLGICs are not limited solely to GABAA receptors [41–44] and the modulatory actions of anesthetics on pLGIC family members are not unique to mammalian systems [45, 46].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [41] Forman, 2015, Anesthetics target interfacial transmembrane sites in nicotinic acetylcholine receptors, Neuropharmacology source

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    • cites [42] Mihic, 1997, Sites of alcohol and volatile anaesthetic action on GABA(A) and glycine receptors, Nature source

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    • cites [43] Howard, 2014, Seeking structural specificity: direct modulation of pentameric ligand-gated ion channels by alcohols and general anesthetics, Pharmacol. Rev. source

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    • cites [44] Burgos, 2016, Structure and pharmacologic modulation of inhibitory glycine receptors, Mol. Pharmacol. source

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    • cites [45] Nury, 2011, X-ray structures of general anaesthetics bound to a pentameric ligand-gated ion channel, Nature source

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    • cites [46] Heusser, 2018, Allosteric potentiation of a ligand-gated ion channel is mediated by access to a deep membrane-facing cavity, Proc. Natl. Acad. Sci. USA source

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    Premisecitation

    Mice lacking CaV3.1 channels show delayed induction of isoflurane anesthesia but unchanged steady-state anesthetic requirements.

    “mice lacking CaV3.1 channels present with delayed induction of isoflurane anesthesia, though their steady-state anesthetic requirements remain unaltered [13].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [13] Petrenko, 2007, Mutation of alpha1G T-type calcium channels in mice does not change anesthetic requirements for loss of the righting reflex and minimum alveolar concentration but delays the onset of anesthetic induction, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anesthetics stabilize HCN channels in their closed conformation, and actions at HCN1 receptors are thought to contribute to volatile anesthetic hypnosis.

    “Anesthetics stabilize HCN channels in their closed conformation. Such actions, especially at HCN1 receptors, are thought to contribute to the hypnotic properties of volatile anesthetics [62].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Zhou, 2015, HCN1 channels contribute to the effects of amnesia and hypnosis but not immobility of volatile anesthetics, Anesth. Analg. source

      Not checked in the free run.

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    Premisecitation

    Volatile anesthetic modulation of CaV3.1 channels in midline thalamic nuclei alters thalamocortical rhythms in mice; under identical isoflurane, CaV3.1 knockout mice show decreased slow-wave EEG and increased burst suppression.

    “Volatile anesthetic-induced modulation of CaV3.1 channel function in midline thalamic nuclei alters thalamocortical rhythms in mice. Under identical isoflurane exposures, compared to sibling controls, CaV3.1 knock-out mice exhibit decreased slow-wave EEG activity, which is often associated with hypnosis, and increased EEG burst suppression, which typifies states of deeper anesthesia [68].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [68] Timic Stamenic, 2019, Alterations in oscillatory behavior of central medial thalamic neurons demonstrate a key role of CaV3.1 isoform of T-channels during isoflurane-induced anesthesia, Cereb. Cortex source

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    Premisecitation

    Volatile anesthetics modulate macroscopic conductance, opening probability, and inactivation of voltage-gated potassium channels.

    “Volatile anesthetics are known to modulate macroscopic conductance, opening probability, and likelihood of inactivation of voltage-gated potassium channels [53].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [53] Li, 2018, Regulatory effect of general anesthetics on activity of potassium channels, Neurosci. Bull. source

      Not checked in the free run.

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    Premisenone given

    The pLGIC family is conserved in eukaryotes and prokaryotes and includes anion- and cation-conducting channels.

    “The pLGIC family, which is conserved across both eukaryotes and prokaryotes, consists of both anion- and cation-conducting channels.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Shaker potassium channel mutants in fruit flies show a 25-50% right-shift in volatile anesthetic dose-response and can exit anesthesia at doses where wild-type siblings remain anesthetized and immobile.

    “These flies display a resistant, right-shift in their volatile anesthetic dose-response curves of roughly 25%−50% but, more remarkably, are capable of exiting states of anesthesia at doses in which their wild-type siblings remain fully anesthetized and immobile [54–57].”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [54] Friedman, 2010, A conserved behavioral state barrier impedes transitions between anesthetic-induced unconsciousness and wakefulness: evidence for neural inertia, PLoS One source

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    • cites [55] Tinklenberg, 1991, Analysis of anesthetic action on the potassium channels of the Shaker mutant of Drosophila, Ann. NY Acad. Sci. source

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    • cites [56] Walcourt, 2001, Blockage of one class of potassium channel alters the effectiveness of halothane in a brain circuit of Drosophila, Anesth. Analg. source

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    • cites [57] Weber, 2009, Increased volatile anesthetic requirement in short-sleeping Drosophila mutants, Anesthesiology source

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  • Classified as probably not a substantial claim.

    Premisereasoning
    § The Biology of General Anesthesia from Paramecium to Primate

    Sleep incurs profound risks and opportunity costs, making its evolutionary persistence puzzling.

    “Like anesthesia, sleep is a state that at first glance should arguably have been selected against because it also incurs identically profound risks and opportunity costs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    T-type calcium channels are important for cell excitability, are expressed in mammalian brain including thalamus, and are especially sensitive to clinical doses of volatile anesthetics.

    “T-type calcium receptors play an important role in cell excitability, are expressed in the mammalian brain in many regions (including the thalamus), and are especially sensitive to clinical doses of volatile anesthetics [65].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Takenoshita, 1991, Halothane blocks low-voltage-activated calcium current in rat sensory neurons, J. Neurosci. source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisenone given

    HCN channels are expressed in mammals and invertebrates, and Drosophila have only one HCN channel.

    “HCN channels are expressed not only in mammals, but also in invertebrates. Although there are four genes that encode mammalian HCN channel subunits, Drosophila have only a single HCN channel.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    The K2P family includes mammalian homologues activated by anesthetics and others inhibited by anesthetics.

    “Subsequent work led to the discovery of the tandem pore potassium channel (K2P) family, which contains mammalian homologues that are activated by anesthetics [48]) as well as those that are inhibited by anesthetics [49, 50].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [48] Andres-Enguix, 2007, Determinants of the anesthetic sensitivity of two-pore domain acid-sensitive potassium channels: molecular cloning of an anesthetic-activated potassium channel from Lymnaea stagnalis, J. Biol. Chem. source

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    • cites [49] Franks, 2004, The TREK K2P channels and their role in general anaesthesia and neuroprotection, Trends Pharmacol. Sci. source

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    • cites [50] Patel, 1999, Inhalational anesthetics activate two-pore-domain background K+ channels, Nat. Neurosci. source

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  • May combine two claims.

    Premisecitation

    Clinical concentrations of volatile anesthetics do not markedly impair sodium currents in squid or crayfish giant axons but significantly depress axonal conduction in mammalian small unmyelinated hippocampal fibers.

    “Although clinical concentrations of volatile anesthetics do not markedly impair sodium currents in squid or crayfish giant axons, they significantly depress axonal conduction in mammalian, small unmyelinated hippocampal fibers [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Mikulec, 1998, Halothane depresses action potential conduction in hippocampal axons, Brain Res. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mutations that enhance presynaptic release cause volatile anesthetic resistance, while those that impair release cause hypersensitivity.

    “In general, mutations that enhanced presynaptic release led to volatile anesthetic resistance, whereas those that impaired release produced a hypersensitive phenotype [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] van Swinderen, 1999, A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Localized infusion of KV1 channel inhibitors into the central thalamus of rodents reverses ongoing sevoflurane or desflurane anesthesia at steady-state, suggesting these channels help set arousal thresholds across evolutionarily distant species.

    “Localized infusion of KV1 channel inhibitors into the central thalamus of rodents reverses ongoing sevoflurane or desflurane anesthesia at steady-state [59, 60], arguing that these channels play an important role in establishing arousal thresholds across evolutionarily distant species.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [59] Alkire, 2009, Thalamic microinfusion of antibody to a voltage-gated potassium channel restores consciousness during anesthesia, Anesthesiology source

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    • cites [60] Lioudyno, 2013, Shaker-related potassium channels in the central medial nucleus of the thalamus are important molecular targets for arousal suppression by volatile general anesthetics, J. Neurosci. source

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    Premisecitation

    Deletion of TASK-1 and TASK-3 in mice is linked to partial volatile anesthetic resistance; loss of TASK-3 reduces halothane sensitivity, stabilizes wakefulness, and slows transitions into sleep.

    “Although deletion of TASK-1 and TASK-3 channels in mice is also associated with partial resistance to volatile anesthetics, the specific loss of TASK-3 not only reduces sensitivity to halothane, it also appears to stabilize the awake state and slows transitions into states of endogenous sleep [51, 52].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [51] Lazarenko, 2010, Motoneuronal TASK channels contribute to immobilizing effects of inhalational general anesthetics, J. Neurosci. source

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    • cites [52] Pang, 2009, An unexpected role for TASK-3 potassium channels in network oscillations with implications for sleep mechanisms and anesthetic action, Proc. Natl. Acad. Sci. USA source

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    Premisecitation

    Anesthetics directly inhibit firefly and bacterial luciferase and modulate ligand-gated receptors, voltage-gated ion channels, leak channels, cytoskeleton, signaling proteins, and mitochondria, with conservation across phylogenetic kingdoms.

    “A renewed search for molecular targets of anesthetics uncovered direct inhibition not only of firefly and bacterial luciferase, but a host of modulatory actions affecting ligand-gated neurotransmitter receptors, voltage-gated ion channels, and channels mediating leak currents, as well as intracellular effects on the cytoskeleton, intracellular signaling proteins, and mitochondria that are conserv”
    Quote in the paperSubstantial claim

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    Premisecitation

    In mice, complex I subunit mutations yield comparable hypersensitivity to volatile anesthetics; in humans with complex I disorders, they yield severe hypersensitivity to volatile anesthetic hypnosis.

    “Mutations affecting complex I subunits produce homologous hypersensitivity to volatile anesthetics in mice as well as profound hypersensitivity to volatile anesthetic hypnosis in humans afflicted by complex I disorders.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Anesthetics cause microtubule-based molecular motors such as kinesin to reversibly detach from the microtubule lattice and disrupt transport of vesicles, proteins, and organelles to synapses.

    “They can also cause microtubule-based molecular motors, such as kinesin, to reversibly fall off the microtubule lattice and thus disrupt transport of vesicles, proteins, and organelles to synapses [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Woll, 2018, An allosteric propofol-binding site in kinesin disrupts kinesin-mediated processive movement on microtubules, J. Biol. Chem. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A syntaxin gain-of-function mutation increasing synaptic activity in flies causes volatile anesthetic resistance when targeted to wake-promoting neurons but hypersensitivity when targeted to sleep-promoting neurons.

    “the use of a syntaxin gain-of-function mutation that increases synaptic activity in flies leads to volatile anesthetic resistance when targeted to wake-promoting neurons but anesthetic hypersensitivity when targeted to sleep-promoting neurons [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] Kottler, 2013, A sleep/wake circuit controls isoflurane sensitivity in Drosophila, Curr. Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Volatile anesthetics reversibly disrupt interactions of NMDA and AMPA receptors with scaffolding proteins, independently altering volatile anesthetic requirements.

    “volatile anesthetics reversibly disrupt the interactions of NMDA and AMPA receptors with scaffolding proteins. This independently alters volatile anesthetic requirements.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Tao, 2008, Effect of disrupting N-methyl-d-aspartate receptor-postsynaptic density protein-95 interactions on the threshold for halothane anesthesia in mice, Anesthesiology source

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    • cites [90] Fang, 2003, Synaptic PDZ domain-mediated protein interactions are disrupted by inhalational anesthetics, J. Biol. Chem. source

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  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Conserved brain networks that control sleep-wake states exist.

    “there are also conserved networks in the brain that have evolved to control sleep-wake states.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The gas-1 mutation is a hypomorphic form of a conserved nuclear-encoded complex I subunit, with reduced electron transfer into oxidative phosphorylation.

    “gas-1 was found to be a hypomorphic allele of a highly conserved, nuclear-encoded subunit of complex I, exhibiting impaired ability to shuttle electrons into mitochondrial oxidative phosphorylation [91].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Kayser, 1999, GAS-1: a mitochondrial protein controls sensitivity to volatile anesthetics in the nematode Caenorhabditis elegans, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Anesthetics bind to tubulin and destabilize microtubules.

    “Anesthetics bind to tubulin, causing microtubules to destabilize [84, 85].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [84] Pan, 2007, Halothane binding proteome in human brain cortex, J. Proteome Res. source

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    • cites [85] Emerson, 2013, Direct modulation of microtubule stability contributes to anthracene general anesthesia, J. Am. Chem. Soc. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In vivo relevance of anesthetic action on the cytoskeleton is validated in tadpoles showing increased anesthetic resistance with microtubule-stabilizing drugs and suggested in humans.

    “The in vivo relevance of anesthetic action on the cytoskeleton has been validated in tadpoles that demonstrate increased anesthetic resistance in the presence of microtubule-stabilizing drugs and also suggested in humans [85, 87].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Emerson, 2013, Direct modulation of microtubule stability contributes to anthracene general anesthesia, J. Am. Chem. Soc. source

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    • cites [87] Linganna, 2015, Taxane modulation of anesthetic sensitivity in surgery for nonmetastatic breast cancer, J. Clin. Anesth. source

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  • May combine two claims.

    Interpretationreasoning

    The sleep-anesthesia connection appears evolutionarily linked to both generation and regulation of sleep.

    “the sleep-anesthesia connection appears to be linked across evolution both to the generation and regulation of sleep.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Interpretationreasoning

    In multicellular organisms, all actions of general anesthetics appear to affect synaptic function, even though different agents use distinct molecular targets.

    “all actions in multicellular organisms would appear to affect synaptic function”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In rats, damaging neurons in this region raises wakefulness while reducing NREM and REM sleep.

    “Lesioning neurons in this region also increases wakefulness in rats at the expense of NREM and REM sleep [123].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [123] Lanir-Azaria, 2018, Enhanced wakefulness following lesions of a mesopontine locus essential for the induction of general anesthesia, Behav. Brain Res. source

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  • May combine two claims.

    Premisecitation

    Drosophila exposed to isoflurane show uncoupling of neural activity from movement at lower doses and cessation of movement at higher doses correlated with local field potential characteristics.

    “Drosophila exposed to isoflurane demonstrate an uncoupling of neural activity patterns from movement at lower doses and cessation of movement at higher doses that correlate with local field potential characteristics [155].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [155] van Swinderen, 2006, A succession of anesthetic endpoints in the Drosophila brain, J. Neurobiol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats, isoflurane causes some networks to reorganize while certain global network properties remain.

    “isoflurane anesthesia induces an organizational shift of particular networks in the rat brain, while maintaining certain global network features [135].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [135] Liang, 2012, Intrinsic organization of the anesthetized brain, J. Neurosci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The thalamus is a critical neuroanatomical target of general anesthetics in mammals and has been proposed as a switch for anesthetic state transitions.

    “The thalamus has long been considered a critical neuroanatomical target of general anesthetics in mammals and has been proposed as a “switch” for anesthetic state transitions [126].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [126] Alkire, 2000, Toward a unified theory of narcosis: Brain imaging evidence for a thalamocortical switch as the neurophysiologic basis of anesthetic-induced unconsciousness, Conscious. Cogn. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exogenous locus coeruleus activation primes emergence from isoflurane anesthesia but cannot antagonize continuous isoflurane anesthesia.

    “Exogenously activating the locus coeruleus primes the brain for emergence from isoflurane anesthesia, without being able to antagonize a continuous isoflurane anesthetic [116].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [116] Vazey, 2014, Designer receptor manipulations reveal a role of the locus coeruleus noradrenergic system in isoflurane general anesthesia, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Impairing adrenergic signaling from locus coeruleus increases volatile anesthetic potency, facilitating entry into and impairing exit from hypnosis.

    “Impairing adrenergic signaling from this nucleus increases the potency of volatile anesthetics—facilitating entry into and impairing exit from hypnotic states [120].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [120] Hu, 2012, Hypnotic hypersensitivity to volatile anesthetics and dexmedetomidine in dopamine beta-hydroxylase knockout mice, Anesthesiology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Anesthetic actions may map onto two dimensions: subcortical effects depress level of consciousness, while thalamocortical/corticocortical effects degrade content.

    “it has been argued that anesthetic actions map on to these two dimensions, with effects in subcortical systems depressing level of consciousness and effects in thalamocortical and/or corticocortical systems degrading or disrupting the content of consciousness [125].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Mashour, 2017, Bottom-up and top-down mechanisms of general anesthetics modulate different dimensions of consciousness, Front. Neural Circuits source

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  • May combine two claims.

    Interpretationreasoning

    Anesthetic mechanisms across species likely reduce to principles of molecular target action, network-level events, and a final common pathway of impaired information transmission and communication across the network.

    “anesthetic mechanisms must likely be reduced to principles involving (1) action at molecular targets, resulting in (2) network-level events, with a final common pathway converging on (3) impaired information transmission and communication across the network.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Some molecular targets for general anesthetics are shared by animals and plants.
    • Rests on an assumption: Network and information-exchange properties do not depend on their physical instantiation.

  • May combine two claims.

    Interpretationreasoning

    Activation of wake-promoting neurons during emergence does not prove that inhibition of the same population occurred during induction, that such inhibition was causal for induction, or that experimental reactivation matches spontaneous emergence activity.

    “activation of wake-promoting neurons during emergence does not necessitate that inhibition of the same population occurred during induction of anesthesia, that potential inhibition was causal with respect to the induction of anesthesia, or that experimental reactivation recapitulates spontaneous changes in activity that occur during emergence.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Prefrontal, posterior parietal, and cingulate regions are posited to form a global neuronal workspace critical to consciousness, and impairment of this workspace can account for traits of the anesthetized state.

    “These particular brain regions are important because they are posited to constitute a global neuronal workspace that is critical to consciousness [145], the impairment of which can account for traits of the anesthetized state [146].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [145] Dehaene, 2011, Experimental and theoretical approaches to conscious processing, Neuron source

      Not checked in the free run.

    • cites [146] Mashour, 2018, Highways of the brain, traffic of the mind, Anesthesiology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The cross-species framework is biologically plausible because some molecular targets are shared by animals and plants and because network and information properties do not depend on physical instantiation.

    “This is a biologically plausible approach because there are molecular targets that are conserved across animals and plants, and the properties of networks and information exchange hold independently of the particular physical instantiation (e.g., neural network of a mammalian brain vs. electrical network of a plant).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Some molecular targets for general anesthetics are shared by animals and plants.
    • Rests on an assumption: Network and information-exchange properties do not depend on their physical instantiation.

  • May combine two claims.

    Premisecitation

    In Drosophila, feedforward connectivity from lower-order to higher-order structures is associated with faster frequencies, while feedback connectivity from higher-order to lower-order is associated with slower frequencies.

    “As in mammalian brain systems, there were faster frequencies associated with feedforward directed connectivity (from lower-order to higher-order) and slower frequencies associated with feedback directed connectivity (from higher-order to lower-order).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [156] Cohen, 2018, Isoflurane impairs low-frequency feedback but leaves high-frequency feedforward connectivity intact in the fly brain, eNeuro source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In C. elegans, isoflurane induces desynchronization of neuronal dynamics and reduced surrogates of information exchange, similar to human EEG phenotypes.

    “isoflurane was found to induce desynchronization of neuronal dynamics and reduced (surrogates of) information exchange [157], which is strikingly similar to EEG-based phenotypes in humans.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [157] Awal, 2018, Breakdown of neural function under isoflurane anesthesia: in vivo, multineuronal imaging in Caenorhabditis elegans, Anesthesiology source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    General anesthetic molecular targets are known to be conserved in mammals, fruit flies, and worms.

    “There is a known conservation of molecular targets for general anesthetics across mammalian systems, fruit flies, and worms.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    It is possible that general anesthetics share a network-level action that lowers network efficiency and makes information exchange unfavorable.

    “it is conceivable that there could be a common network-level effect of general anesthetics that reduces network efficiency, ultimately resulting in conditions that are inhospitable to information exchange.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Information exchange is necessary for coordinating sensation and response in an organism's interaction with its environment.

  • May combine two claims.

    Interpretationreasoning

    Common molecular or functional targets may account for shared anesthetic responses, with network-level effects as a generalizable mechanistic framework across species.

    “Common molecular or functional targets might account for these shared responses, with network-level effects representing a generalizable mechanistic framework across species.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Some molecular targets for general anesthetics are shared by animals and plants.
    • Rests on an assumption: Network and information-exchange properties do not depend on their physical instantiation.
    • Rests on an assumption: Information exchange is necessary for coordinating sensation and response in an organism's interaction with its environment.
49 of 49

  • The paper relies on this without support.

    Some molecular targets for general anesthetics are shared by animals and plants.

    “there are molecular targets that are conserved across animals and plants”

  • The paper relies on this without support.

    Network and information-exchange properties do not depend on their physical instantiation.

    “the properties of networks and information exchange hold independently of the particular physical instantiation”

  • The paper relies on this without support.

    Information exchange is necessary for coordinating sensation and response in an organism's interaction with its environment.

    “Such information exchange is critical to the coordination of events that allows both the sensation and response that is characteristic of a bidirectional relationship with the environment.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Inhalational anesthetics bind promiscuously at hydrophobic pockets in a variety of proteins in the brain and spinal cord.

    “Inhalational anesthetics bind promiscuously at hydrophobic pockets in a variety of proteins in the brain and spinal cord.”

    From A quantum microtubule substrate of consciousness is experimentally supported and solves the binding and epiphenomenalism problems (2025) · cites this paper as Kelz and Mashour 2019

    The paper describes volatile anesthetic binding as promiscuous and identifies multiple protein targets, including receptors in the mammalian brain (opening discussion; “Ligand gated ion channels”; pages unavailable). But it presents occupancy of hydrophobic protein pockets as a hypothesis, not an established binding mechanism, and the passages do not establish the claim specifically for proteins in the spinal cord. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • The same anesthetic vapors that make us unconscious also reversibly slow or halt motility in single-celled organisms and plants.

    “Remarkably, the same anesthetic vapors that make us unconscious also reversibly slow or halt motility in single-celled organisms and plants (Kelz and Mashour 2019, Yokawa et al. 2019).”

    From A quantum microtubule substrate of consciousness is experimentally supported and solves the binding and epiphenomenalism problems (2025) · cites this paper as Kelz and Mashour 2019

    The Cytoskeleton section says volatile anesthetics impair motility in single-celled organisms. The review also describes anesthetic effects in plants, but the passages do not establish that plant motility slows or halts, or that the claimed motility effects are reversible. Page numbers were not available in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

Cites

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Related

Authors
Kelz, M. B., & Mashour, G. A.
Affiliations
  • University of Pennsylvania (US)
  • University of Michigan (US)
Corresponding author
  • Kelz, Max B.
  • Mashour, George A.
ORCID
Venue
Current Biology
Publisher
Elsevier BV
Published
2019-11
Volume
29
Issue
22
Pages
R1199-R1210
ISSN
0960-9822 (ISSN-L)
DOI
10.1016/j.cub.2019.09.071
PMC
PMC6902878
OpenAlex
W2985893387
Semantic Scholar
ec3ab06759d9911f51356b2ec0a0a99c1706ab39
Cited by
151
References
162
Citations by year
2026: 19 · 2025: 22 · 2024: 24 · 2023: 39 · 2022: 14 · 2021: 19 · 2020: 13 · 2019: 1
FWCI
2.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Current Biology (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institutes of Health
Topics
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Anesthesia and Sedative Agents
  • Life Sciences › Neuroscience › Developmental Neuroscience › Anesthesia and Neurotoxicity Research
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
general anesthesia, anesthetic mechanisms, loss of consciousness, anesthetic targets, cytoskeleton, ion channels, mitochondria, neural network function, modularity, Paramecium, plants, primates, cross-species comparison
MeSH terms
Anesthesia, Anesthesia, General, Anesthetics, Animals, Brain, Mammals, Paramecium, Plants, Primates, Unconsciousness, Anesthetics, General

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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