A Hypothesis on the Origin and Evolution of the Response to Inhaled Anesthetics

Abstract

An evolutionary narrative explaining why organisms respond to inhaled anesthetics is proposed. It is conjectured that organisms today respond to inhaled anesthetics because their ion channels are sensitive to inhaled anesthetics by virtue of common descent from ancestral, anesthetic-sensitive ion channels in one-celled organisms (i.e., that the response to anesthetics did not arise as an adaptation of the nervous system, but rather of ion channels that preceded the origin of multicellularity). This sensitivity may have been refined by ongoing selection at synapses in multicellular organisms. In particular, it is hypothesized that (1) the beneficial trait that was selected for in one-celled organisms was the coordinated response of ion channels to compounds that were present in the environment which influenced the conformational equilibrium of ion channels (2) that this coordinated response prevented the deleterious consequences of entry of positive charges into the cell, thereby increasing the fitness of the organism (3) that these compounds (which may have included organic anions, cations, and zwitterions as well as uncharged compounds) mimicked inhaled anesthetics in that they were interfacially active, and modulated ion channel function by altering bilayer properties coupled to channel function. The proposed hypothesis is consistent with known properties of inhaled anesthetics. In addition, it leads to testable experimental predictions of nonvolatile compounds having anesthetic-like modulatory effects on ion channels and in animals, including that of endogenous compounds that may modulate ion channel function in health and disease. The latter included metabolites which are elevated in some types of end stage organ failure, and genetic metabolic diseases. Several of these predictions have been tested and proved to be correct. Implications A hypothesis for the origin and evolution of the response to inhaled anesthetics is offered, and experimental predictions of this theory are made.

From membrane excitability to metazoan psychology

“…Clearly, a simple equation between the total volume of cation influx and the level of conscious awareness will not hold and the temporal sequencing of neuronal events across brain systems needs to be considered. Finally, indication that sentience results from the influx of cations during the action potential comes from anesthesiology: the modes of action of most volatile anesthetics are known to entail the blocking of cation influx and/or the facilitation of anion influx [70], either of which will reduce the incidence of neuronal firing and the associated sentience. Sonner [70,71] and Mashour and Alkire [72], among others, noted that the induction of, and emergence from, general anesthesia provide well-controlled conditions for exploring questions concerning the brain localization of ion fluxes and the related states of awareness.…”

Isoflurane Impairs Low-Frequency Feedback but Leaves High-Frequency Feedforward Connectivity Intact in the Fly Brain

“…Indeed, the cellular and molecular machinery that makes up the nervous system is largely conserved across species (Littleton and Ganetzky, 2000), such that the cellular and molecular targets of general anesthetics are also likely to be conserved (Sonner, 2008; van Swinderen and Kottler, 2014; Zalucki and van Swinderen, 2016). Whether the conserved cellular and molecular targets of general anesthetics also translate to conserved system-level general anesthetic effects, such as reduced FB, is currently unknown.…”

Understanding of anesthesia – Why consciousness is essential for life and not based on genes

“…The father of experimental biology, Claude Bernard, performed numerous experimental studies which allowed him to conclude “that all life is defined by the susceptibility to anesthesia.” 2,11,12 Claude Bernard's paradigm is still valid today as all organisms, even prokaryotic bacteria, are sensitive to anesthetics 8,9,12,13-15 . Sub-cellular organelles such as mitochondria and chloroplasts are sensitive to anesthetics as well, 16-21 which is in line with the prokaryotic sensitivity of both membranes and proteins recorded in bacteria 14,22-24 .…”

“…As discussed by James Sonner, the variability in response to anesthetics is extremely small in comparison to other drugs 8,31 . Moreover, the wide molecular diversity of compounds acting as anesthetics is very large, and additionally, the mystery of universal sensitivity of all living organisms to these compounds remains.…”