Current Concepts on the Mechansim of General Anesthetics

Joseph F. Antognini, M.D.

University of California, Davis

The last decade has seen a tremendous increase in our understanding of anesthetic mechanisms. A variety of analytical and biological techniques have allowed us to probe anesthetic mechanisms at the molecular, receptor, cellular and systems level. While this growth of knowledge has brought us closer than ever to understanding how anesthetics work, we are still woefully short on critical information.

Most investigators have abandoned non-specific theories of action, e.g., the Meyer-Overton hypothesis, to explain how anesthetics act. There are enough exceptions to this rule that other mechanisms now seem more plausible. These exceptions include selectivity of stereoisomers, the cut-off effect and non-immobilizers. The demonstration that anesthetics can affect proteins directly, including water soluble proteins, suggests that more specific sites are possible. The focus is now on proteins that are neurophysiologically relevant—the GABA_A receptor, glutamate receptors and the glycine receptor, among others. There is intense interest in the GABA_A receptor, as it mediates inhibition, which is likely a key way in which anesthesia is produced. Mutagenesis of the GABA_A receptor (and other receptors) has helped to identify specific sites where anesthetics are likely to produce an effect. Nonetheless, leaving no rock unturned, investigators are examining previously unlikely candidate sites, including the Na+ channel. In the past, the Na+ channel would have been low on the list, but emerging evidence now suggests that anesthetic action at a Na+ channel could impact pre-synaptic events, and thus impede synaptic transmission.

It is difficult to piece together the various molecular and cellular data within the context of a functioning intact organism. That is, how does an action at a GABA_A receptor translate into the various clinical end-points, such as amnesia, unconsciousness and immobility? Is the brain more important to anesthetic action than the spinal cord? Evidence has emerged in the last decade suggesting that the spinal cord is the site where some anesthetics (e.g., volatile) produce immobility—but where in the spinal cord (and does it matter)? Why do some anesthetics, such as thiopental, appear to produce immobility mostly via an action in brain? Ongoing research hopefully will answer these important questions.

Non-invasive imaging techniques are now being used to determine where (and how) anesthetics work in humans. Positron emission tomography and functional magnetic resonance imaging studies indicate that anesthetics do not produce a non-specific global depression of brain structures, but have specific sites of action, such as thalamus and the reticular activating system.

While much work has been done, and many questions have been addressed, there are still more questions unanswered. Hopefully, once we understand how anesthetics work we can begin rational, knowledge driven design of newer and safer anesthetics.

References:

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4.      Hemmings HC Jr, Akabas MH, Goldstein PA, Trudell JR, Orser BA, Harrison NL. Emerging molecular mechanisms of general anesthetic action.
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