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ANESTHETIC PHARMACOLOGY

Mice with Glycine Receptor Subunit Mutations Are Both Sensitive and Resistant to Volatile Anesthetics

Joseph J. Quinlan, MD^*, Carolyn Ferguson, BS^*, Katherine Jester, BS^*, Leonard L. Firestone, MD^*, and Gregg E. Homanics, PhD^*

Departments of *Anesthesiology and Pharmacology, University of Pittsburgh, Pennsylvania

Address correspondence and reprint requests to Gregg E. Homanics, PhD, University of Pittsburgh, Department of Anesthesiology, W1356 Biomedical Science Tower, Pittsburgh, PA 15261. Address e-mail to homanicsge{at}anes.upmc.edu

We used two mouse lines with glycine receptor mutations to determine whether glycine receptors might play an important role in anesthetic responses in vivo. Spastic (spA) mutants were slightly more sensitive (P = 0.02) to enflurane in the loss-of-righting reflex assay (50% effective concentration [EC₅₀] = 1.17 ± 0.06 atm for controls versus 0.97 ± 0.06 atm for spA) but were also substantially more resistant (P = 0.01) to enflurane in the tail clamp assay (EC₅₀ = 1.96 ± 0.10 atm for controls versus 2.58 ± 0.25 atm for spA). spA mice were also more sensitive to halothane (P < 0.001) in the loss-of-righting reflex assay (EC₅₀ = 0.81 ± 0.03 atm for controls versus 0.57 ± 0.04 atm for spA), but the responses of mutant and control mice to tail clamp in the presence of halothane were similar. Spasmodic control and mutant mice did not differ in their responses to the two drugs. Sleep time was substantially longer in both mutant mouse lines after injection of three hypnotics (midazolam, pentobarbital, and ethanol). Our results suggest a complex involvement of glycinergic pathways in mediating anesthetic responses. Greater sensitivity to the hypnotic effect of enflurane, halothane, midazolam, pentobarbital, and ethanol in mutant mice with diminished glycinergic capacity suggests that glycinergic activity is inversely related to hypnosis, whereas resistance to enflurane in the tail clamp assay suggests that glycinergic activity potentiates the minimum alveolar anesthetic concentration response. Halothane seems to share some, but not all, of enflurane’s mechanisms, indicating that not all volatile anesthetics modulate glycinergic pathways equally.

IMPLICATIONS: We tested two mouse lines with glycine receptor mutations to determine whether glycine receptors might play an important role in anesthetic responses in vivo. Both sensitivity and resistance to common anesthetics were observed in mutant mice, depending on the behavioral end-point evaluated.

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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