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ANESTHETIC PHARMACOLOGY

Isoflurane-Induced Changes in Righting Response and Breathing Are Modulated by RGS Proteins

Eduardo E. Icaza, BS^*, Xinyan Huang, PhD, Ying Fu, PhD, Richard R. Neubig, MD, PhD, Helen A. Baghdoyan, PhD^*, and Ralph Lydic, PhD^*

From the Departments of *Anesthesiology, and Pharmacology, University of Michigan, Ann Arbor, Michigan.

Address correspondence and reprint requests to Ralph Lydic, PhD, Department of Anesthesiology, University of Michigan, 7433 Medical Science Building I, 1150 W. Medical Center Dr., Ann Arbor, MI 48109-5615. Address e-mail to rlydic{at}med.umich.edu.

BACKGROUND: Recent evidence suggests that G protein–coupled receptors, especially those linked to G_i, contribute to the mechanisms of anesthetic action. Regulator of G protein signaling (RGS) proteins bind to activated G_i and inhibit signal transduction. Genomic knock-in mice with an RGS-insensitive G_i2 G184S (G_i2 GS) allele exhibit enhanced G_i2 signaling and provide a novel approach for investigating the role of G_i2 signaling and RGS proteins in general anesthesia.

METHODS: We anesthetized homozygous G_i2 GS/GS and wild-type (WT) mice with isoflurane and quantified time (in seconds) to loss and resumption of righting response. During recovery from isoflurane anesthesia, breathing was quantified in a plethysmography chamber for both lines of mice.

RESULTS: G_i2 GS/GS mice required significantly less time for loss of righting and significantly more time for resumption of righting than WT mice. During recovery from isoflurane anesthesia, G_i2 GS/GS mice exhibited significantly greater respiratory depression. Poincaré analyses show that GS/GS mice have diminished respiratory variability compared with WT mice.

CONCLUSION: Modulation of G_i2 signaling by RGS proteins alters loss and resumption of wakefulness and state-dependent changes in breathing.