Over 50 years ago, the reasonable hypothesis was presented that the hypnosis caused by a general anesthetic was related to cellular energetics.1 The model was tested early on by comparing the levels of high-energy phosphates (e.g., adenosine triphosphate [ATP] and creatine phosphate) in central nervous system tissue, finding no change in anesthetized animals compared with controls.2 Despite other more positive research findings, the lack of change in ATP essentially ended early interest in intermediary metabolism as a mechanism for general anesthesia. In retrospect, however, this loss in interest was premature, the result of a superficial understanding of the complexities of both metabolism and of the general anesthetic state.
The involvement of metabolism in the anesthetized state is certainly consistent with many features of general anesthesia, such as muscle relaxation, decreased oxygen consumption, and hypothermia. Furthermore, both injectable and inhalational anesthetics clearly depressed mitochondrial respiration and seemed to preferentially partition in this organelle as well.3 Proteomic studies implicated many mitochondrial proteins as targets of both inhalational and injectable anesthetics, including certain subunits of the electron transport complexes, Kreb cycle enzymes, and substrate channels such as the voltage-dependent anion channel.4 Most convincing have been the genetic studies in Caenorhabditis elegans and now in mice that have implicated complex 15,6 activity as a functional target of several anesthetics, including isoflurane. Recent proteomic studies using a propofol-like photolabel7 confirm binding to a specific subunit of complex 1 in mammalian brain. Moreover, children with mitochondriopathies, subsequently localized to complex 1, have dramatically enhanced sensitivity to sevoflurane.8
Thus, it is clear that anesthetics bind specifically to relevant mitochondrial proteins and depress energy production and that endogenous disruption of energy production via genetics enhances sensitivity to anesthetics. Thus, it should come as no surprise that exogenous factors that depress energy production can also enhance sensitivity to anesthetics. For example, it is clear that hypothermia enhances sensitivity to both volatile and injectable anesthetics. Hydrogen sulfide, a mitochondrial complex 4 inhibitor, also enhances sensitivity to anesthetics.9 Both hypothermia and hydrogen sulfide can induce a sleep- or hibernation-like state on their own,10 but not surgical anesthesia. Thus, the demonstration of an ability of 2-deoxy-D-glucose, a glucose analog that competes for substrate of hexokinase, and 3-nitropropionic acid, a compound that inhibits succinate dehydrogenase, to both deplete ATP production and modestly enhance isoflurane sensitivity11 nicely caps decades of prior work. It also provides more potential sites than just complex 1. It would be of considerable interest to determine whether all the major end points of general anesthetic exposure (amnesia, hypnosis, movement, etc.) are shifted in parallel, as it has become clear that different subsets of anesthetic targets may contribute more to some end points than to others. It would also be of interest to determine whether the same degree of shift is seen with all general anesthetics, again to discern how specific this effect is.
Given that modulation of intermediary metabolism by such diverse tactics can alter anesthetic sensitivity, the real question is whether energy production is a direct, on-pathway effect of anesthetics, or is it an indirect effect that modulates stability of the conscious state in parallel with effects produced by other anesthetic targets? The answer to this question will emerge as results from the studies suggested above, and others, emerge.
Name: Roderic G. Eckenhoff, MD.
Contribution: This author helped write the manuscript.
Attestation: Roderic G. Eckenhoff approved the final manuscript.
Name: Philip G. Morgan, MD.
Contribution: This author helped write the manuscript.
Attestation: Philip G. Morgan approved the final manuscript.
This manuscript was handled by: Markus W. Hollmann, MD, PhD, DEAA.
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