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Unlocking the Mechanisms of Anesthesia

Roth, Sheldon H. PhD*; Miller, Keith W. DPhil; Orser, Beverley A. MD, PhD‡§; Urban, Bernd W. PhD

doi: 10.1213/ANE.0000000000001427
Editorials: Editorial
Free

Published ahead of print July 22, 2016.

From the *Departments of Physiology & Pharmacology and Anaesthesia, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada; Department of Anesthesia and Critical Care, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Departments of Anesthesia and §Physiology, University of Toronto, Toronto, Ontario, Canada; and Klinik fuer Anaesthesiologie, Universitaetsklinikum Bonn, Bonn, Germany.

Published ahead of print July 22, 2016.

Accepted for publication April 29, 2016.

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Sheldon H. Roth, PhD, Departments of Physiology & Pharmacology and Anaesthesia, University of Calgary, Cumming School of Medicine, 3330 Hospital Dr NW, Calgary, Alberta, Canada T2N 4N1. Address e-mail to shroth@ucalgary.ca.

Many thanks to the Editorial Board for agreeing to dedicate this Special Issue of Anesthesia & Analgesia to the 2015 International Mechanisms of Anesthesia Conference (MAC 2015). The articles published in this issue reflect the large number of topics that were presented at the conference. MAC meetings are held every 5 years and host investigators who seek to understand how general anesthetics alter brain function. MAC 2015 was the ninth in a series of anesthesia conferences that was founded by the late Dr. Raymond B. Fink (1914–2000). Dr. Fink, an anesthesiologist at the University of Washington, organized the first conferences in Seattle, WA, in 1974 and again in 1979. Subsequent meetings were organized by Sheldon Roth and Keith Miller (1984, 1990, 1997) at the University of Calgary, Alberta, Canada. From there, the meetings moved to Bonn, Germany (2001); Nara, Japan (2005); and Toronto, Canada (2010). The history of the MAC has been described in detail in the Editorial of a Special Issue of the Canadian Journal of Anesthesia.1

The Charter of the MAC Conferences states: “the aim of the conference is to enhance the understanding of the mechanisms of action of general anesthetics. The meeting should consist of symposia attended by all participants; two or more workshops in the evenings and poster sessions integrated into the meeting schedule.” The recent conference (MAC 2015) was held at the Gustav-Stresemann-Institut in Bonn, Germany, on June 17 to 19, 2015. The organizers were Keith W. Miller (Harvard University, Boston, MA, USA), Beverley A. Orser (University of Toronto, Canada), Sheldon H. Roth (University of Calgary, Canada), and Bernd W. Urban (University of Bonn, Germany, local organizer). The program and other details can be viewed on the conference website.2 A total of 164 registrants from 14 countries (Australia, Austria, Belgium, Canada, China, Finland, France, Germany, United Kingdom, Israel, Japan, New Zealand, Switzerland, and the United States) were in attendance. Most importantly, and in the spirit of MAC meetings, the relatively isolated venue and design of the conference center ensured that informal and spirited discussions continued throughout the day and evening.

For the first time, the MAC Organizing Committee based the scientific program on proposals submitted from the scientific community. This approach welcomed a variety of scientific perspectives. Thus, the conference topics, listed on the conference website,2 reflect those that participants deemed most important, not simply those of the Scientific Organizing Committee.

Advances in our understanding of the mechanisms of action of general anesthetics, from molecular to behavioral levels, were highlighted. The conference opened on June 17 with Symposium 1: “Identification of anesthetic-binding sites and mechanisms on ligand-gated channels” and was followed by Symposium 2: “Role of GABAA receptors in anesthetic action.” Symposium 3: “Anesthetic sites and effects on voltage-gated ion channels” and Symposium 4: “Transmitter-gated CNS chloride channels—new targets for emerging drugs combating chronic pain” completed the day. Evening sessions consisted of 5 workshops that discussed neuroprotection, interactions with channel gating, modulation of cortical networks, extrasynaptic γ-aminobutyric acid type A (GABAA) receptors, and molecular and cellular pathways impacting pathophysiology and disease.

The second day began with Symposium 5: “Anesthetic mechanisms in memory, consciousness and sleep” followed by Symposium 6: “Zeitgeist and anesthetic research: is the reductionist approach passé?” The afternoon sessions consisted of Symposium 7: “General anesthetic action: generalized suppression or dedicated network?” and Symposium 8: “Developmental neurotoxicity: mechanisms, phenotype and clinical relevance.” The 5 evening workshops debated the topics: modulation of thalamocortical circuits, anesthetic neurotoxicity in developing and aging brains, the influence of external stimuli on unconsciousness, side effect targets of anesthetics, and if bench to bedside happens. On the final day, presentations of Symposia 9 and 10 addressed “Neural circuit mechanisms of general anesthesia” and Symposium 11 “Memory formation during anesthesia.”

Several key topics were presented throughout the conference. At the molecular level, the first crystal structure of a human GABAA receptor heralds the dawn of an era that suggests the rational design of general anesthetics may become a reality. The promise of this advance is emphasized by molecular pharmacology and photolabeling that revealed the possibility to develop general anesthetics that selectively target specific sites on subpopulations of GABAA receptors based on the subunit composition of the receptors. The extension of these concepts to other ion channels and anesthetic targets suggests a bright future for these lines of study.

At the cellular level, both the number of ion channels that are plausible targets for anesthetics and the knowledge about how these channels alter neurotransmission continues to grow. Cation channels include Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, potassium channel subtypes, and sodium channels. The role of GABAA receptors in anesthesia is being re-evaluated in light of results that show different subpopulations of GABAA receptors have different drug affinities, kinetic properties, and patterns of distribution. Furthermore, these different subunit populations confer different behavioral actions of the anesthetics. In addition, GABAA receptors must reside on the surface of neurons to be activated by GABA. Studies show that the trafficking to and stabilization of GABAA receptors in the plasma membrane are dynamically regulated. Changes in the number of GABAA receptors on the surface of neurons dramatically alter the pharmacological response of neurons, adding a new layer of complexity to the response of the brain to anesthetic drugs.

Advances in technology are propelling central nervous system studies forward. As an example, optogenetic techniques allow light-activated ion channels to be expressed in specific cell types or brain regions. Simply flicking a light switch can activate these exogenous proteins, and they in turn modify the function of neurons. This powerful method offers unprecedented temporal, regional, and cell type-specific control of neuronal and network excitability. Similarly, exogenous proteins are now being introduced into discrete brain regions to determine whether the anesthetic and sedative drugs interact with specific circuits such as sleep and arousal pathways.

Concerns regarding the potential neurotoxic effects of anesthetics in the developing brain remain at the forefront. Numerous preclinical studies have shown that exposure of the developing brain to anesthetics leads to apoptosis, a reduction in the number of spines, additional morphological changes, and cell death. Postanesthetic behavioral deficits have also been observed. The relevance of these preclinical results to clinical outcomes in patients remains an evolving area of intense investigation. Recent studies suggest that a single, brief exposure to the anesthetic may be well tolerated, whereas prolonged or repeated exposures are of greater concern. During development, there may be a critical window of vulnerability and dose threshold for injury. Increasing evidence also suggests that subtle neurocognitive deficits in adult animals can persist long after the drugs have been eliminated. Such changes may contribute to delirium and postoperative cognitive deficits in the early postoperative period. Strategies are being examined to mitigate toxicity such as the use of xenon, dexmedetomidine, lithium, and other potential neuroprotectants.

The relationship between synchronized network rhythms and behavior was another topic of interest. The role of arousal pathways and the relationship to sleep share some common features. Also, discrete brain regions mediate some but not all the behavioral endpoints associated with anesthesia. Coordinated and integrated activity between regionally diverse networks has been explored with electroencephalography and brain imaging. Remarkable advances in neuroimaging in humans have offered insights into the pathways that mediate pain or drug-induced altered levels of consciousness. For example, such studies are being used to explain why some subjects are more sensitive than others to painful stimuli.

The Symposium, “From bench to bedside: does it happen?,” clearly demonstrated that research in anesthetic mechanisms has progressed to a level where the findings are beginning to directly impact clinical practice. In fact, not only does the translation from bench to bedside occur, but the reverse also takes place, suggesting that future anesthetic research will be characterized by a continuous bouncing back and forth between bench and bedside.

Considering the remarkable advances that have occurred during the past 5 years, the next MAC conference promises to be an exciting and informative meeting. MAC 2020 is currently being planned, the location and dates to be determined in the near future. Until there is a specific website for MAC 2020, check the website www.mac2015.uni-bonn.de for details.

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DISCLOSURES

Name: Sheldon H. Roth, PhD.

Contribution: This author helped complete this manuscript.

Name: Keith W. Miller, DPhil.

Contribution: This author helped complete this manuscript.

Name: Beverley A. Orser, MD, PhD.

Contribution: This author helped complete this manuscript.

Name: Bernd W. Urban, PhD.

Contribution: This author helped complete this manuscript.

This manuscript was handled by: Gregory J. Crosby, MD.

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REFERENCES

1. Miller KW, Orser BA, Roth SH. Mechanisms of anesthesia: past, present, and a glimpse into the future. Can J Anaesth. 2011;58:131134, 134138.
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