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ANESTHETIC PHARMACOLOGY

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

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

From the *University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; Department of Anesthesia and Perioperative Care, University of California, San Francisco; 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 ₁ß₂ and anesthetic-resistant ₁(S270I)ß₂ -amino-butyric acid (GABA) type A receptor, and GABA to a homomeric ₁ wild type and anesthetic-resistant 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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