Mouse strain modestly influences minimum alveolar anesthetic concentration and convulsivity of inhaled compounds.
In this study, we measured the minimum alveolar anesthetic concentration (MAC) in several mouse strains, including strains used in the construction of genetically engineered mice. This is important because defined genetic modifications are used increasingly to test mechanisms of inhaled anesthetic action, and background variability in MAC can potentially influence the interpretation of these studies. We investigated the effect of strain on MAC for desflurane, isoflurane, halothane, ethanol, the experimental anesthetic 1-chloro-1,2,2-trifluorocyclobutane, and convulsive 50% effective dose (the dose required to produce convulsions in 50% of animals) of the nonimmobilizer 1,2-dichlorohexafluorocyclobutane. These drugs were studied in eight inbred strains, including both laboratory and wild mouse strains (129/J, 129/SvJ, 129/Ola Hsd, C57BL/6NHsd, C57BL/6J, DBA/2J, Spret/Ei, and Cast/Ei), one hybrid strain (B6129F2/J, derived from the C57BL/6J and 129/J strains), and one outbred strain (CD-1). To test our ability to detect effects in a genetically modified mouse, we compared these data with those for a mouse lacking the gamma (neuronal) isoform of the protein kinase C gene (PKCgamma). We also assessed whether amputating the tail tip of mice (a standard method of obtaining tissue for genetic analysis) increased MAC (e.g., by sensitization of the spinal cord). MAC and convulsant 50% effective dose values differed modestly among strains, with a range of 17% to 39% from the lowest to highest values for MAC using conventional anesthetics, and up to 48% using the experimental anesthetic 1-chloro-1,2,2-trifluorocyclobutane. Convulsivity to the nonimmobilizer varied by 47%. Amputating the tail tip did not affect MAC. PKCgamma knockout mice had significantly higher MAC values than control animals for isoflurane, but not for halothane or desflurane, which implies that protein phosphorylation by PKCgamma can alter sensitivity to isoflurane.


CONCLUSIONS
Anesthetic potency differs by modest amounts among inbred, outbred, wild, and laboratory mouse strains. Absence of the neural form of protein kinase C increases minimum alveolar anesthetic concentration for isoflurane, indicating that protein phosphorylation by the gamma-isoform of protein kinase C (PKCgamma) can influence the potency of this anesthetic.
Sonner
J M
JM
Department of Anesthesia, University of California, San Francisco 94143-0464, USA. jim_sonner@quickmail.ucsf.edu
Gong
D
D
Li
J
J
Eger
E I
EI
Laster
M J
MJ
D000769:Anesthesia, Inhalation; D000777:Anesthetics / Q000008:administration & dosage / Q000494:pharmacology; D018685:Anesthetics, Inhalation / Q000008:administration & dosage* / Q000494:pharmacology; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology; D017402:Chlorofluorocarbons / Q000008:administration & dosage / Q000494:pharmacology; D003292:Convulsants / Q000008:administration & dosage* / Q000494:pharmacology; D003503:Cyclobutanes / Q000008:administration & dosage / Q000494:pharmacology; D000077335:Desflurane; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology; D006221:Halothane / Q000008:administration & dosage / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics; D007530:Isoflurane / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains / Q000235:genetics; D018345:Mice, Knockout / Q000235:genetics; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics; D013116:Spinal Cord / Q000187:drug effects
D000777:Anesthetics; D018685:Anesthetics, Inhalation; D002492:Central Nervous System Depressants; D017402:Chlorofluorocarbons; D003292:Convulsants; D003503:Cyclobutanes; D007527:Isoenzymes; C090640:1,2-dichloro-1,2,3,3,4,4-hexafluorocyclobutane; D000431:Ethanol; C107485:1-chloro-1,2,2-trifluorocyclobutane; D000077335:Desflurane; D007530:Isoflurane; D011493:Protein Kinase C; D006221:Halothane