Mechanisms of general anesthesia.
OBJECTIVE
Anesthetics influence a wide variety of transmitter- and voltage-gated ion channels in the mammalian central nervous system. At the molecular level, the gamma-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 GABA(A) receptor function.


RESULTS
Anesthetics bind to discrete selective binding sites on GABA(A) receptors--a discovery that challenges lipid-based theories of anesthesia. Not all GABA(A) receptors are equally sensitive to anesthetics because positive allosteric modulation is critically dependent on receptor subunit composition. Moreover, GABA(A) 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 GABA(A) receptors. Finally, synthetic neurosteroids are being developed as improved general anesthetics.


CONCLUSIONS
Detailed insights into anesthetic-GABA(A) receptor interactions have resulted in intense efforts to develop safer drugs that selectively target subtypes of GABA(A) receptors.
Orser
Beverley A
BA
Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada. Beverley.orser@utoronto.ca
Canning
Kevin J
KJ
Macdonald
John F
JF