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It's what we do everyday. why can't we explain how it works?

In this issue of the journal, Dr John Carmody reviews some aspects of the mechanisms of general anaesthesia (1). Because we give general anaesthetics every day, it is easy to forget that we are witnesses to a strange and apparently miraculous phenomenon. No other drug therapy in medicine causes such a comprehensive shut-down in the function of a whole organ system. No other drug therapy even approaches general anaesthesia in its reliability and effectiveness--which is well in excess of 99%. There have been thousands of published studies over the last century that have tried to explain how general anaesthesia works. However, our understanding of the neurobiology of general anaesthesia is still embarrassingly superficial. General anaesthesia is a subject about which we know so much but understand so little.

Clinicians should be aware that in the last five years there has been considerable new experimental work published, elaborating on various new aspects of the neuroscientific basis of general anaesthesia (2-5). Dr Carmody's article does not purport to be a traditional comprehensive review of this vast subject, but instead to re-evaluate some old ideas in the light of this new information. A number of these old concepts are very topical. The first is the old chestnut of whether general anaesthetics interact primarily with lipids (Meyer-Overton) (6) or proteins (Franks-Lieb) (7). It is surely erroneous to formulate this question as "either" lipid "or" protein. Clearly proteins are heterogeneous molecules with hydrophobic pockets; and conversely, the surrounding medium in which the protein is embedded is crucial to the proper function of the protein. Clinicians have learned about proteins from physiology textbooks, which typically show diagrams of very stationary (protein) blobs sitting in a bilaminar sea of membrane lipid. It is not appreciated that, for proteins to work properly, they need to be able to move and jiggle freely. They need to be able to both swim around in the lipid membrane and to undergo countless changes in internal configuration every second. This applies even to such apparently 'structural' proteins as ligand-gated ion channels (8). It is easy to envisage hydrophobic anaesthetic molecules impeding this 'dance' of the proteins. Second, Linus Pauling's proposal of clathrates has received new impetus, in the light of recent work showing the importance of 'structured water' in cell biology. (For a very readable introduction to these iconoclastic ideas, I would recommend the book: "Cells, Gels and the Engines of Life" by Pollack (9)). The role of general anaesthesia-induced perturbation of intracellular structured water is a field of research that is wide open, but it is easy to imagine that hydrophobic anaesthetic molecules might disrupt or distort the precise arrangements of water molecules that exist within cells. Last, Dr Carmody has reopened ideas as to the mechanisms by which general anaesthetic drugs act within neurons to disrupt memory consolidation. Modern neuroscience has teased out the details of many of the mechanisms of memory storage (e.g. involving intracellular protein kinases). How do general anaesthetic drugs affect these mechanisms?

There are, however, some important issues that are not addressed in Dr Carmody's article. General anaesthesia is not just the disruption of consciousness. Anaesthesia is a syndrome that includes amnesia, suppression of somatic and autonomic responsiveness, and probably unconsciousness. (It must be recognised that there is an extreme utilitarian view taken by Eger and others, that positively excludes unconsciousness from the definition of general anaesthesia (10).) Consciousness is almost certainly a phenomenon that requires some form of self co-ordinated interaction amongst widely separated populations of neurons--involving large portions of the brain. Drugs act at the molecular level. If we want to explain how general anaesthetics disrupt consciousness we must be able to follow an unbroken chain of causation from the smallest to the largest scale. If we show that the anaesthetic drug produces a certain molecular effect, we must then be able to demonstrate how this effect alters neuronal function, and thence how the dynamics of whole brain function is affected--manifest as the clinically observed state of general anaesthesia. What is more, using the phraseology of formal logic, this process must be rigorously shown to be "sufficient" and "necessary". This implies that every time the particular molecular alteration is observed to occur, the state of general anaesthesia inevitably results. If there exist counter-examples of the molecular effects occurring, but no state of general anaesthesia resulting, then the purported molecular cause of the anaesthetic is not "sufficient". Conversely, if we can find a case in which general anaesthesia occurred in the absence of the purported molecular mechanism, then the mechanism is not "necessary" for anaesthesia. If, as Dr Carmody has suggested, there are many paths to the state of general anaesthesia, the strict requirement for necessity might not be met.

The development of quantum physics, and hence the understanding of the nature of atomic structure, was arguably the pre-eminent scientific achievement of the 20th century. The proper understanding of the nature of consciousness is the grand scientific quest of the 21st century. We in the profession of anaesthesia know a great deal about consciousness. We turn it on and off many times a day. Are we not beholden to contribute to this quest?

REFERENCES

(1.) Carmody J. Some scientific reflections on possible fundamental mechanisms of general anaesthesia. Anaesth Intensive Care 2009; 37:175-189.

(2.) Eger EI 2nd, Raines DE, Shafer SL, Hemmings HC, Jr, Sonner JM. Is a new paradigm needed to explain how inhaled anesthetics produce immobility? Anesth Analg 2008; 107:832-848.

(3.) Franks NP. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat Rev Neurosci 2008; 9:370-386.

(4.) Grasshoff C, Drexler B, Rudolph U, Antkowiak B. Anaesthetic drugs: linking molecular actions to clinical effects. Curr Pharm Des 2006; 12:3665-3679.

(5.) Rudolph U, Antkowiak B. Molecular and neuronal substrates for general anaesthetics. Nat Rev Neurosci 2004; 5:709-720.

(6.) Meyer H. Theorie der Alkoholnarkose. Arch Exptl Pathol Pharmakol 1899; 42:109-118.

(7.) Franks NP, Lieb WR. Molecular mechanisms of general anaesthesia. Nature 1982; 300:487-493.

(8.) Kusumi A, Ike H, Nakada C, Murase K, Fujiwara T. Singlemolecule tracking of membrane molecules: plasma membrane compartmentalization and dynamic assembly of raft-philic signaling molecules. Semin Immunol 2005; 17:3-21.

(9.) Pollack GH. Cells, Gels and the Engines of Life. A New, Unifying Approach to Cell Function. Seattle, Ebner and Sons, 2002.

(10.) Eger EI 2nd, Sonner JM. Anaesthesia defined (gentlemen, this is no humbug). Best Pract Res Clin Anaesthesiol 2006; 20:23-29.

J. W. Sleigh

Department of Anaesthesia

Waikato Hospital

Hamilton, New Zealand
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Author:Sleigh, J.W.
Publication:Anaesthesia and Intensive Care
Article Type:Editorial
Geographic Code:8NEWZ
Date:Mar 1, 2009
Words:1083
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