Mice with glycine receptor subunit mutations are both sensitive and resistant to volatile anesthetics.
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 [EC(50)] = 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 (EC(50) = 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 (EC(50) = 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.


CONCLUSIONS
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.
Department of Anesthesiology, University of Pittsburgh, W1356 Biomedical Science Tower, Pittsburgh, PA 15261, USA.
Joseph J
JJ
Quinlan
Carolyn
C
Ferguson
Katherine
K
Jester
Leonard L
LL
Firestone
Gregg E
GE
Homanics
D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D004351:Drug Resistance; D004737:Enflurane / Q000494:pharmacology; D000431:Ethanol / Q000097:blood; D005260:Female; D006221:Halothane / Q000494:pharmacology; D008297:Male; D051379:Mice; D010147:Pain Measurement / Q000187:drug effects; D010641:Phenotype; D004856:Postural Balance / Q000187:drug effects; D018009:Receptors, Glycine / Q000235:genetics*; D012890:Sleep / Q000187:drug effects; D013997:Time Factors
D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; C491949:Glrb protein, mouse; D018009:Receptors, Glycine; D000431:Ethanol; D004737:Enflurane; D006221:Halothane