Mechanisms of general anesthesia

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Abstract
Anesthetics influence a wide variety of transmitter- and voltage-gated ion channels in the mammalian central nervous system. At the molecular level, the γ-aminobutyric acid (GABA) subtype A receptor has emerged as a primary therapeutic target. This review highlights recent advances in our understanding of how anesthetics modify GABAA receptor function. Anesthetics bind to discrete selective binding sites on GABAA receptors - a discovery that challenges lipid-based theories of anesthesia. Not all GABAA receptors are equally sensitive to anesthetics because positive allosteric modulation is critically dependent on receptor subunit composition. Moreover, GABAA receptors located in extrasynaptic regions of hippocampal neurons display a greater sensitivity to propofol and benzodiazepines than do receptors located in subsynaptic regions. Enhancement in GABAergic inhibition may not account for all of the behavioral end-points associated with the anesthetic state. In particular, the immobilizing properties of anesthetics may not be solely mediated by GABAA receptors. Finally, synthetic neurosteroids are being developed as improved general anesthetics. Detailed insights into anesthetic-GABAA receptor interactions have resulted in intense efforts to develop safer drugs that selectively target subtypes of GABAA receptors.