General Anesthetic Actions on GABAA Receptors Paul Garcia, Emory University Scott E

General Anesthetic Actions on GABAA Receptors Paul Garcia, Emory University Scott E. Kolesky, Emory University Andrew Jenkins, Emory University Journal Title: Current Neuropharmacology Volume: Volume 8, Number 1 Publisher: Bentham Science Publishers | 2010-03, Pages 2-9 Type of Work: Article | Final Publisher PDF Publisher DOI: 10.2174/157015910790909502 Permanent URL: http://pid.emory.edu/ark:/25593/fkg4m Final published version: http://www.eurekaselect.com/71259/article Copyright information: ©2010 Bentham Science Publishers Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution 2.5 Generic License ( http://creativecommons.org/licenses/by/2.5/), which permits distribution, public display, and publicly performance, distribution of derivative works, making multiple copies, provided the original work is properly cited. This license requires credit be given to copyright holder and/or author. Accessed September 28, 2021 5:01 PM EDT 2 Current Neuropharmacology, 2010, 8, 2-9 General Anesthetic Actions on GABAA Receptors Paul S. Garcia, Scott E. Kolesky and Andrew Jenkins* Departments of Anesthesiology and Pharmacology, Emory University, School of Medicine, Rollins Research Center #5013, 1510 Clifton Rd NE, Atlanta GA, USA Abstract: General anesthetic drugs interact with many receptors in the nervous system, but only a handful of these interactions are critical for producing anesthesia. Over the last 20 years, neuropharmacologists have revealed that one of the most important target sites for general anesthetics is the GABAA receptor. In this review we will discuss what is known about anesthetic – GABAA receptor interactions. Keywords: GABAA Receptor, General Anesthetic, Isoflurane, Desflurane, Sevoflurane, Propofol, Etomidate, Barbiturates. INTRODUCTION administered drugs interact with key sites on cellular proteins in the body which results directly in the alteration in the General anesthetics have been used to relieve pain and function of these proteins, in the present case, neuronal pro- suffering in surgical patients for almost 170 years. Prior to teins that control how information is conveyed through the their discovery, surgery was a traumatic and barbaric affair, nervous system. yet today, it is accepted as a routine and essential part of modern medicine. It is curious therefore, that despite the It is noteworthy that the study of general anesthesia as a technological advances that have been made in perioperative whole, has not immediately lent itself to being accessible to medicine and surgical techniques, the pharmacologic thera- traditional pharmacology; anesthesia is a clinical state where peutics administered by anesthesiologists to render patients a myriad of behavioral endpoints are caused by a group of unconscious, continue to be used without a precise under- drugs that bear no physical resemblance to one another. standing of how they generate the anesthetized state. Nevertheless, it appears that GABAARs are incredibly ac- commodating and possess several binding sites that interact Fortunately, over the last two decades, the intensive use with many of the currently used general anesthetics. Moreo- of the tools of modern molecular pharmacology and neuro- ver, these interactions obey many of the basic principles of science has enabled investigators to understand better than rational pharmacology; the effects of drug on protein are ever before how anesthetic chemicals can alter the function concentration dependent, they are subject to the “ceiling ef- of the nervous system. In this review, we will carefully de- fect”, they are allosteric in nature, the effects are dependent fine what we mean by “anesthesia” and then we will focus on the temperature of the preparation, some compounds ex- on how the currently used anesthetic agents modulate the hibit stereoselectivity and depending on the anesthetic, they function of the GABA receptor (GABA R), the most abun- A A appear to modulate the efficacy and/or the apparent affinity dant fast inhibitory neurotransmitter receptor in the CNS. of the receptor for its endogenous ligand. At the outset, we would like to emphasize that this re- In the following sections, we will define what we under- view is neither historical nor is it exhaustive. We do not in- stand to be “general anesthesia” and how anesthetic drugs tend to review the interaction of every drug used by anesthe- interact with native and mutant GABA Rs. siologists in the Operating Room, past or present, with every A critical binding site in the body. The purpose of this review WHAT IS GENERAL ANESTHESIA? is to summarize some of the key findings that we feel have When Oliver Wendell Holmes first coined the term advanced our understanding of how the currently used general anesthetic drugs interact with their neuronal targets. The anæsthesia in 1846, the word, which literally means a lack of sensation, was used to describe a patient who after inhaling history of anesthetic pharmacology is rich and has played a ether vapor, underwent surgery without any apparent suffer- critical role in our understanding of the anesthetized state ing. Widespread use of the technique and this term followed, and the reader is encouraged to read previous reviews if they describing a state where one or more chemicals were sys- are interested in reviewing the action of disused anesthetics temically administered to “anesthetize” patients, permitting such as halothane, chloroform or ether. Neither shall we dwell on discarded theories of anesthetic action. It is the fer- humane surgery to occur. Arguably one of the greatest breakthroughs in medical history, it is interesting that this vent view of the authors that general anesthesia is no differ- essential component of modern medicine has developed ent from any other pharmacological process: exogenously without a rational theory consistent with modern pharmacology that accounts for the molecular mechanisms of these *Address correspondence to this author at the Departments of Pharmacol- drugs in the human body. ogy and Anesthesiology, Emory University School of Medicine, Rollins Research Center #5013, 1510 Clifton Rd NE, Atlanta GA, 30322-3090, One reason for this is that after more than 160 years of USA; Tel: 404-727-3910; Fax: 404-712-2585; E-mail: [email protected] routine clinical use, there is still no consensus on what singu- 1570-159X/10 $55.00+.00 ©2010 Bentham Science Publishers Ltd. General Anesthetic Actions on GABAA Receptors Current Neuropharmacology, 2010, Vol. 8, No. 1 3 larly defines the anesthetized state. During general anesthe- THEORY OF GENERAL ANESTHETIC ACTION sia, a myriad of events occur in the body that alter motor responses, cognition, sensation and autonomic control. A At the cellular level, anesthetics alter the behavior of neurons, by interacting directly with a small number of ion patient will go from being anxious, to unconscious and im- channels. Under normal conditions, these specialized mem- mobile and back to awake and in light of this, there contin- brane proteins are activated by chemical signals or changes ues to be a debate on which of these effects, or what combi- in the membrane environment. Upon activation, channels nation of these effects are the critical determinants of general change the electrical excitability of neurons by controlling anesthesia. the flow of depolarizing (excitatory) or hyperpolarizing (in- The seminal work by Eger et al. [64], set the benchmark hibitory) ions across the cell membrane via an ion channel in understanding anesthetic actions for almost 50 years. The that is integral with the receptor that senses the initial signal. definition of the Minimum Alveolar Concentration (MAC) General anesthetics primarily act by either enhancing inhibi- places great emphasis on anesthetic induced immobility, as a tory signals or by blocking excitatory signals. It is important read-out for sensation, and less emphasis on processes not to note that none of the current clinical general anesthetics directly linked to the sensation of acute pain and their asso- are selective for a single ion channel. At clinical concentra- ciated motor reflexes. Subsequent research has demon- tions, every anesthetic modulates the function of two or more strated, perhaps not unsurprisingly, that the key sites in the types of channels in the central nervous system. Thus, each nervous system that determine MAC are found in the spinal different anesthetic agent alters neuronal activity by acting in cord [3] and interestingly, may not be critically dependent on differing degrees at multiple sites. GABA Rs [73]. Nevertheless, although MAC may not have A GENERAL ANESTHETICS AND THEIR TARGETS revealed information on the cerebral sites of anesthetic action and anesthetic actions on sensory processing, one of the Currently, there are 5 inhalational and 5 intravenous an- great benefits of the MAC studies was to define a set of drug esthetics used to induce or maintain general anesthesia: Inha- concentrations that are appropriate for use in in vitro studies lational: Nitrous Oxide, Isoflurane, Sevoflurane, Desflurane on potential molecular targets, a giant leap forward for mo- and Xenon. Intravenous: Propofol, Etomidate, Ketamine, lecular pharmacologists interested in understanding how Methohexital and Thiopental. These 10 general anesthetic these drugs induce anesthesia. drugs are often accompanied by sedative benzodiazepines: midazolam, diazepam and lorazepam. For many decades after the inception of general anesthesia,

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