Anesthetics are widely used clinically to produce loss of consciousness, decreased pain perception, antegrade amnesia, and muscle relaxation, so that a range of surgical procedures may be performed. The mechanisms by which anesthetics produce their complex effects are largely unknown. A multistage gene mapping strategy is proposed to identify molecular mechanisms underlying decreased responsiveness to pain after anesthetic administration. LS and SS selected mouse lines will first be characterized for tail flick responses after administration of nitrous oxide isoflurane, ketamine, and morphine. Based on dose and time parameters established with LS and SS mice, LSXSS recombinant inbred (RI) strains will be phenotyped, and provisional QTLs will be identified using an interval mapping method. Confirmation of provisional QTLs identified in RI analyses will be accomplished by statistically based gene mapping in F2 mice, and by characterization of genotypes of extreme scorers in the population. Genetic correlations between drug responses among the strains, and comparison of significant QTLs will provide information with regard to common, perhaps crucial, mechanisms underlying anesthetic effects, and overlap with mechanisms of analgesia produced by the classic opiate, morphine. These studies will provide information for design of safe and more effective anesthetics, and will provide basic information with regard to the molecular genetic underpinnings of complex traits.
