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Role of Voltage-Gated Sodium Channels in the Mechanism of Ether-Induced Unconsciousness

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Role of Voltage-Gated Sodium Channels in the Mechanism of Ether-Induced Unconsciousness 1521-0081/71/4/450–466$35.00 https://doi.org/10.1124/pr.118.016592 PHARMACOLOGICAL REVIEWS Pharmacol Rev 71:450–466, October 2019 Copyright © 2019 by The Author(s) This is an open access article distributed under the CC BY-NC Attribution 4.0 International license. ASSOCIATE EDITOR: LORI L. ISOM Role of Voltage-Gated Sodium Channels in the Mechanism of Ether-Induced Unconsciousness Nicholas Denomme, Jacob M. Hull, and George A. Mashour Departments of Pharmacology (N.D.) and Anesthesiology (G.A.M.), Center for Consciousness Science (N.D., G.A.M.), and Neuroscience Graduate Program (J.M.H., G.A.M.), University of Michigan, Ann Arbor, Michigan Abstract ...................................................................................450 I. Introduction . ..............................................................................450 A. Scope and Relevance . ..................................................................450 B. Historical Background and Clinical Use of the Halogenated Ethers. ...................451 II. Basic Pharmacology and Physicochemical Properties of the Halogenated Ethers .............452 III. Basic Overview of Voltage-Gated Sodium Channel Biology . ...............................452 A. Neuromodulation of Voltage-Gated Sodium Channels ...................................455 IV. Molecular Interactions of Halogenated Ethers with Voltage-Gated Sodium Channels . .......456 V. Structural and Computational Studies Using Prokaryotic Voltage-Gated Sodium Downloaded from Channels ..................................................................................459 VI. Presynaptic Voltage-Gated Sodium Channel Inhibition Leads to Depressed Neurotransmission. ........................................................................460 VII. In Vivo Modulation of Halogenated Ether Anesthesia. .....................................461 A. Modulation of Anesthetic Sensitivity Mediated by Pharmacological Manipulation of by guest on September 28, 2021 Voltage-Gated Sodium Channels. ......................................................461 1. Overlap with Local Anesthetic Mechanism of Action . ...............................461 B. Modulation of Anesthetic Sensitivity Mediated by Genetic Manipulation of Voltage- Gated Sodium Channels................................................................462 VIII. Conclusion. ..............................................................................463 References . ..............................................................................464 Abstract——Despite continuous clinical use for for a mechanistic interaction between halogenated more than 170 years, the mechanism of general anes- ethers and sodium channels in the induction of thetics has not been completely characterized. In this unconsciousness. We conclude with a more integrative review, we focus on the role of voltage-gated sodium perspective of how voltage-gated sodium channels channels in the sedative–hypnotic actions of halogenated might provide a critical link between molecular ethers, describing the history of anesthetic mechanisms actions of the halogenated ethers and the more research, the basic neurobiology and pharmacology distributed network-level effects associated with of voltage-gated sodium channels, and the evidence the anesthetized state across species. I. Introduction both clinical and basic science. From a clinical perspective, there are more than 300 million major surgeries around A. Scope and Relevance the world each year, which typically occur under general Despitemorethan170yearsofclinicaluseand anesthesia (Weiser et al., 2015). Understanding the scientific study, the molecular mechanism of action of structure–activity relationships of anesthetic action can ether anesthesia remains incompletely understood. Char- potentially lead to the development of safer and more acterizing the molecular events by which anesthetic efficacious anesthetic drugs. In addition to the practical agents lead to the loss of consciousness is important for applications, elucidating the molecular mechanisms of Address correspondence to: Dr. George A. Mashour, Department of Anesthesiology, Center for Consciousness Science, University of Michigan Medical School, 1500 E. Medical Center Drive, 1H247 University Hospital, SPC-5048, Ann Arbor, MI, 48109-5048. E-mail: [email protected] https://doi.org/10.1124/pr.118.016592. 450 Sodium Channels and General Anesthesia 451 anesthetic-induced unconsciousness has implications for As halogen chemistry developed, it was found that pharmacology as well as the neurobiology of consciousness a halogenated derivative would greatly reduce the itself. flammability of diethyl ether. In the 1930s, chemists The clinical state of general anesthesia is character- Harold Booth and E. Max Bixby were the first to try ized by the pharmacological induction of amnesia, un- synthesizing a fluorinated anesthetic. Although they consciousness, analgesia, and immobility. General failed with their compound monochlorodifluoromethane, anesthesia is reversible and can be induced by a struc- Booth and Bixby (1932) recognized the importance of turally diverse range of molecules administered either fluorine substitutions in developing a noncombusti- intravenously or by inhalation. A large body of evidence ble volatile anesthetic. Thorough analysis of organic now supports inhaled anesthetics acting on diverse fluoride-based compounds led them to the observation anatomic sites and molecular targets within the ner- that fluorination would improve molecular stability vous system to produce the array of clinical endpoints and toxicity. seen during general anesthesia. This review will focus Earl McBee directed a Manhattan Project initiative to on the class of inhaled anesthetics known as the refine 235U by first converting it to the uranium halogenated ethers and the role that voltage-gated hexafluoride intermediate. His expertise in fluorination sodium channels (VGSCs) play in their mechanism of ultimately resulted in a grant from Mallinckrodt Chem- sedative–hypnotic action. ical Works to produce new fluorinated hydrocarbons as potential anesthetics (Whalen et al., 2005). The McBee group synthesized dozens of compounds, none of which B. Historical Background and Clinical Use of the displayed anesthetic properties. Vanderbilt Pharmacol- Halogenated Ethers ogist Ben Robbins tested the fluorinated hydrocarbons. In 1540, German botanist and physician Valerius Although none succeeded, his analysis was optimistic, Cordus heated a mixture of triply-distilled wine (ethanol) and he encouraged further exploration in the area with vitriol (sulfuric acid) (Cordus, 1561). Cordus named (Robbins, 1946). the sweet-smelling remains “oleum dulci vitrioli,” which is A University of Maryland pharmacology group led by Latin for the sweet oil of vitriol. Cordus’ssweetoilwas John Krantz published dozens of articles in The Journal diethyl ether, commonly referred to as ether. of Pharmacology & Experimental Therapeutics, and For the following three centuries after Cordus’s initial Anesthesiology from 1940 to 1961, investigating the discovery, ether was primarily used recreationally. properties of hundreds of ethers and hydrocarbons Although not made public, Dr. Crawford Long performed (Calverley, 1986). The 40th study in their series surgeries under ether at his private practice in Jefferson, reported the effects of trifluoroethyl vinyl ether Georgia, from 1842 to 1846. He did not publish his (Krantz et al., 1953). In 1954, the Ohio Chemical and findings until 1849 (Long, 1849). The widespread use of Surgical Company introduced trifluoroethyl vinyl ether as a general anesthetic was ushered in on October ether (fluroxene) into clinical use as the first halogenated 16, 1846 in the first successful public demonstration of ether for general anesthesia (Calverley, 1986). Al- surgery under diethyl ether anesthesia by dentist William though much safer than ether, fluroxene was poten- T. G. Morton (Bigelow, 1846). Morton’snew“miracle” gas tially flammable at supraclinical concentrations. Letheon enabled renowned American surgeon John Col- Additionally, it caused severe nausea and vomiting. lins Warren to remove a neck tumor from a patient In 1974, after 20 years on the market, fluroxene was without any pain or knowledge of the operation at a time withdrawn. This came shortly after it was discovered when, without such interventions, surgical patients could that fluroxene was metabolized into multiple toxic be completely conscious of these major traumatic inter- metabolites, including trifluoroethanol (Cascorbi and ventions (Fenster, 2001). Singh-Amaranath, 1972). Methoxyflurane was intro- Subsequently, diethyl ether was used to achieve duced in 1960, sustaining popularity for a decade general anesthesia for over 75 years. Ether had many (Artusio et al., 1960). Its high lipid solubility caused shortcomings, notably its flammable and explosive long postoperative recovery times. Reports of methoxy- properties. The dangerous properties of diethyl ether flurane causing dose-related nephrotoxicity due to arise from a combination of factors, including its low inorganic fluoride began to emerge (Crandell et al., boiling point, high vapor pressure, and tendency to form 1966). It too was withdrawn from the market. explosive peroxides. The necessity for a safer and non- Throughout the 1960s and 1970s, the chemistry group flammable alternative led to a wealth of research into led by Ross Terrell synthesized hundreds of fluori- general anesthetics in the first
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