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ANESTHETIC PHARMACOLOGY

Gamma-Aminobutyric Acid_A Receptors Do Not Mediate the Immobility Produced by Isoflurane

Yi Zhang, MD^*, James M. Sonner, MD, Edmond I Eger, II, MD^*, Caroline R. Stabernack, MD^*, Michael J. Laster, DVM^*, Douglas E. Raines, MD, and R. Adron Harris, PhD

*Department of Anesthesia and Perioperative Care, University of California, San Francisco, California, Harvard Medical School, Boston, Massachusetts, and the University of Texas, Austin, Texas

Address correspondence and reprint requests to James M. Sonner, MD, Department of Anesthesia, S-455, University of California, San Francisco, CA 94143–0464. Address email to sonnerj{at}anesthesia ucsf.edu.

Many inhaled anesthetics enhance the effect of the inhibitory neurotransmitter gamma aminobutyric acid (GABA), supporting the view that the GABA_A receptor could mediate the capacity of inhaled anesthetics to produce immobility in the face of noxious stimulation (i.e., MAC, the minimum alveolar concentration required to suppress movement in response to a noxious stimulus in 50% of subjects). However, only limited in vivo data support the relevance of the GABA_A receptor to MAC. In the present study we used two findings to test for the relevance of this receptor to immobilization for isoflurane: 1) differences among anesthetics in their capacity to enhance the response of receptor expression systems to GABA: isoflurane (considerable enhancement), xenon (minimal enhancement), and cyclopropane (minimal enhancement); and 2) studies showing that the spinal cord mediates MAC for isoflurane. If GABA_A receptors mediate isoflurane MAC, then their blockade in the spinal cord should increase isoflurane MAC more than cyclopropane or xenon MAC and the MAC increase should be proportional to the in vitro enhancement of the GABA_A receptor. To test this thesis, isoflurane, cyclopropane, or xenon MAC was determined in rats during intrathecal infusion of artificial cerebrospinal fluid (aCSF) via chronically implanted catheters. Then MAC was redetermined during infusion of 1 µL/min aCSF containing either 0.6 or 2.4 mg/mL picrotoxin, which noncompetitively blocks GABA_A receptors. There was no consistent increase in MAC consequent to increasing the picrotoxin dose from 0.6 to 2.4 µg/min, which suggests that maximal blockade of GABA_A receptors in the spinal cord had been achieved. Picrotoxin infusion increased MAC approximately 40% with all anesthetics. This indicates that GABA release in the spinal cord influences anesthetic requirement. However, the increase did not consistently differ among anesthetics and did not correlate with in vitro enhancement of GABA_A receptors by these anesthetics. This supports the view that GABA_A receptors do not mediate immobilization for isoflurane.

IMPLICATIONS: Although in vitro studies demonstrate that isoflurane enhances the effect of gamma aminobutyric acid (GABA) on GABA_A receptors, results from the present in vivo work indicate that the GABA_A receptor does not mediate the immobility produced by isoflurane.

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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