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Anesth Analg 2007;105:386-392
© 2007 International Anesthesia Research Society
doi: 10.1213/01.ane.0000267258.17197.7d

ANESTHETIC PHARMACOLOGY

Anesthetic-Like Modulation of a {gamma}-Aminobutyric Acid Type A, Strychnine-Sensitive Glycine, and N-Methyl-d-Aspartate Receptors by Coreleased Neurotransmitters

Pavle S. Milutinovic, MS*, Liya Yang, PhD{dagger}, Robert S. Cantor, PhD{ddagger}, Edmond I. Eger, II, MD{dagger}, and James M. Sonner, MD{dagger}

From the *University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; {dagger}Department of Anesthesia and Perioperative Care, University of California, San Francisco; {ddagger}Department of Chemistry, Dartmouth College, Hanover, New Hampshire.

Address correspondence to James M. Sonner, MD, Department of Anesthesia and Perioperative Care, Room S-455i, University of California, San Francisco, CA 94143-0464. Address e-mail to sonnerj{at}anesthesia.ucsf.edu.

INTRODUCTION: A mechanism of anesthesia has recently been proposed which predicts that coreleased neurotransmitters may modulate neurotransmitter receptors for which they are not the native agonist in a manner similar to anesthetics.

METHODS: We tested this prediction by applying acetylcholine to a NR1/NR2A N-methyl-d-aspartate receptor, glycine to a wild-type {alpha}1ß2 and anesthetic-resistant {alpha}1(S270I)ß2 {gamma}-amino-butyric acid (GABA) type A receptor, and GABA to a homomeric {alpha}1 wild type and anesthetic-resistant {alpha}1 S267I glycine receptor. Receptors were expressed in Xenopus laevis oocytes and studied using two-electrode voltage clamping.

RESULTS: We found inhibition of N-methyl-d-aspartate receptor function by acetylcholine, enhancement of glycine receptor function by GABA, and enhancement of GABA type A receptor function by glycine. As expected of compounds with anesthetic activity, GABA showed far less potentiation (enhancement) of the function of the anesthetic-resistant S267I glycine receptor than that of the wild-type receptor. Glycine potentiated the function of wild-type GABA type A receptors but inhibited the function of the anesthetic-resistant S270I GABA type A receptor.

CONCLUSIONS: These results show that neurotransmitters that are coreleased onto anesthetic-sensitive receptors may modulate the function of receptors for which they are not the native agonist via an anesthetic-like mechanism. These findings lend support to a recent theory of anesthetic action.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press
Copyright © 2007 by the International Anesthesia Research Society.