This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (10) Citing Articles via Google Scholar Google Scholar Articles by Quinlan, J. J. Articles by Homanics, G. E. Search for Related Content PubMed PubMed Citation Articles by Quinlan, J. J. Articles by Homanics, G. E. Related Collections Pharmacology

---

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.

This article has been cited by other articles:

				B. T. Welsh, B. E. Goldstein, and S. J. Mihic Single-Channel Analysis of Ethanol Enhancement of Glycine Receptor Function J. Pharmacol. Exp. Ther., July 1, 2009; 330(1): 198 - 205. [Abstract] [Full Text] [PDF]

				E. I. Eger II, D. E. Raines, S. L. Shafer, H. C. Hemmings Jr, and J. M. Sonner Is a New Paradigm Needed to Explain How Inhaled Anesthetics Produce Immobility? Anesth. Analg., September 1, 2008; 107(3): 832 - 848. [Abstract] [Full Text] [PDF]

				M. M. Sedensky and P. G. Morgan Genetics and the Evolution of the Anesthetic Response Anesth. Analg., September 1, 2008; 107(3): 855 - 858. [Full Text] [PDF]

				J. G. Bovill Anesthetic Pharmacology: Reflections of a Section Editor Anesth. Analg., November 1, 2007; 105(5): 1186 - 1190. [Full Text] [PDF]

				P. Nagele, L. B. Metz, and C. M. Crowder Nitrous oxide (N2O) requires the N-methyl-D-aspartate receptor for its action in Caenorhabditis elegans PNAS, June 8, 2004; 101(23): 8791 - 8796. [Abstract] [Full Text] [PDF]

				J. M. Sonner, J. F. Antognini, R. C. Dutton, P. Flood, A. T. Gray, R. A. Harris, G. E. Homanics, J. Kendig, B. Orser, D. E. Raines, et al. Inhaled Anesthetics and Immobility: Mechanisms, Mysteries, and Minimum Alveolar Anesthetic Concentration Anesth. Analg., September 1, 2003; 97(3): 718 - 740. [Abstract] [Full Text] [PDF]

				L. L. Thio, A. Shanmugam, K. Isenberg, and K. Yamada Benzodiazepines Block {alpha}2-Containing Inhibitory Glycine Receptors in Embryonic Mouse Hippocampal Neurons J Neurophysiol, July 1, 2003; 90(1): 89 - 99. [Abstract] [Full Text] [PDF]