Towards a Comprehensive Understanding of Anesthetic Mechanisms of Action: A Decade of Discovery

Abstract

Significant progress has been made in the 21st century towards a comprehensive understanding of the mechanisms of action of general anesthetics, coincident with progress in structural biology and molecular, cellular, and systems neuroscience. This review summarizes important new findings that include target identification through structural determination of anesthetic binding sites, details of receptors and ion channels involved in neurotransmission, and the critical roles of neuronal networks in anesthetic effects on memory and consciousness. These recent developments provide a comprehensive basis for conceptualizing pharmacological control of amnesia, unconsciousness, and immobility.

Keywords: consciousness; cortex; hippocampus; hypothalamus; ion channel; memory.

Figure 1.. General anesthetics bind and alter GABA_A receptor function at distinct sites.

(A) Structure of the homopentameric prokaryotic Gloeobacter violaceus ligand-gated ion channel (GLIC) in an ion conducting conformation determined by x-ray crystallography (PDB ID 3EAM) [13]. Shown in side-view (above) and in cross-section (below, enlarged), the locations of known anesthetic binding sites are labeled; these include a pore lining site, an intersubunit site located between neighboring subunits, and an intrasubunit site bounded by the transmembrane (TM), domains of a given subunit (shown in blue). Note that in the absence of anesthetic, a membrane lipid (black spheres) is present at the intrasubunit anesthetic binding site. Image created using PyMOL 1.5 (Schrödinger; New York, NY). (B) Homology model of the αβγ GABA_A receptor, showing amino acid residues labeled by photolabel mimics of intravenous (Azi-propofol, Azi-etomidate, mTFD-MPPB) and volatile (Azi-isoflurane, Azi-sevoflurane) general anesthetics. Most residues are located in the more hydrophobic TM region of the receptor, and most are intersubunit residues. Note the multiplicity of sites and that different anesthetics label both distinct and overlapping residues, despite the fact that all of these anesthetics affect this receptor as either direct agonists or co-agonists. mTFD-MPPB (S-1-methyl-5-propyl-5-(m-trifluoromethyl-di azirynylphenyl) barbituric acid), is a photoreactive analog of the convulsant barbiturate S-1-methyl-5-phenyl-5-propyl barbituric acid (S-MPPB), which inhibits GABA_A-R responses at the same concentration at which the anesthetic isomer, R-MPPB, potentiates responses. Image created using VMD software (available from: https://www.ks.uiuc.edu/) [125]. (C–F) Structures derived by x-ray crystallography of the conductive conformation of wild type GLIC in the presence of propofol (yellow, PDB ID 3P50), desflurane (purple, PDB ID 3P4W), or two molecules of bromoform (a brominated derivative of chloroform, red, PDB ID 4HFH), and of an ethanol sensitized GLIC F14’A mutant in the presence of ethanol (green, PDB ID 4HFE) [13, 14].

Figure 2.. General anesthetics “disconnect” functional brain networks.

(A) Effect of sevoflurane anesthesia on functional connectivity. (Top) There is widespread thalamocortical (TC) connectivity as measured by functional magnetic resonance imaging (fMRI) during the waking state (gray voxels; horizontal plane, anterior to the right). Sevoflurane produces a pronounced reduction in connectivity, especially with frontal cortex (white voxels) at the highest sevoflurane concentration. There is a progressive increase in connectivity (gray voxels) as sevoflurane concentration decreases. (B) Sevoflurane decreases directed connectivity as measured by EEG symbolic transfer entropy (STE). Loop color encodes direction of information flow (red: rostrocaudal, blue: caudorostral); scale bar indicates degree of connectivity as measured by STE, where an STE value = 0 indicates balanced bidirectional flow of information. Legend and figure modified with permission from [126].

Fig 3.. Different anesthetics produce different electroencephalogram signatures.

(A) Power maps of 10.3 Hz activity in a human subject, demonstrating “anteriorization” of the α component of the EEG spectrogram with increasing levels of propofol-induced sedation. Baseline indicates the subject is at rest and Levels 1–5 indicate increasing propofol concentrations (as shown). Here, anteriorization is demonstrated by the shift of the α signal (in red-orange) from posterior to anterior regions of the brain. (B) Spectograms from posterior (top) and frontal (bottom) electrodes. With increasing propofol concentrations there is progressive loss of signal in the α bandwidth (8–12 Hz; in yellow) in the posterior electrode with its pronounced appearance in the anterior electrode. The δ signal (in red-orange) is initially present only in anterior brain regions, but as the level of sedation increases, both the α and δ signals are seen anteriorly. Scale bar is the power of the EEG signal, where power is in μV². A and B modified with permission from [92]. (C) In unprocessed electroencephalogram (EEG) waveforms, anesthetic-specific differences are slight. Sevoflurane is representative of volatile anesthetics, which have similar EEG patterns at equipotent concentrations. x(D) Different anesthetics produce different spectrographic patterns. Electroencephalogram signatures can be related to the molecular targets and the neural circuits at which the anesthetics act to create altered states of arousal. Again, note the α-δ pattern of activity (in red-orange) for both propofol and sevoflurane. Molecular targets for which there are compelling in vivo and in vitro data are shown. C and D modified with permission from [127].