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Nitrous oxide antinociception in BXD recombinant inbred mouse strains and identification of quantitative trait loci
R M Quock1, J L Mueller, L K Vaughn
1Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford 61107-1897, USA. raymondq@uic.edu
Abstract:
Among inbred mouse strains, DBA/2 mice are unique because of their poor responsiveness to nitrous oxide (N2O) antinociception. As a first step towards identifying candidate genes involved in determining antinociceptive responsiveness to N2O, male mice from the DBA/2 strain, the more responsive C57BL/6 strain, their B6D2F1 offspring, and 22 BXD recombinant inbred (RI) strains derived from DBA/2 and C57BL/6 mice were exposed to N2O and evaluated using the acetic acid abdominal constriction test. When exposed to 70% N2O, C57BL/6, DBA/2 and B6D2F1 mice exhibited antinociceptive responses of 78, 22 and 55%, respectively. The BXD RI strains demonstrated varying degrees of responsiveness to N2O. Cluster analysis revealed one cluster of 16 strains approximating the C57BL/6 progenitor (61.9-100% antinociceptive response to 70% N2O) and another of six strains around the DBA/2 progenitor (9.1-40% antinociceptive response to 70% N2O). The robust strain differences permitted screening the strain means with 1492 marker loci previously mapped in BXD RI strains. Using a QTL analysis specifically tailored to existing mouse RI strains, we found associations at the 0.01 level on seven chromosomes with the most promising marker loci being Il2ra, Hbb, Hmg1rs7 and Gsl5 on chromosomes 2, 7, 16 and 19, respectively (P < 0.002).
Insights
DBA/2 mice show poor response to nitrous oxide (N2O) pain relief, unlike C57BL/6 mice. Genetic analysis of BXD mice identified seven chromosomes linked to N2O antinociception, aiding in understanding pain relief mechanisms.
Area of Science:
- Neuroscience
- Genetics
- Pharmacology
Background:
- Nitrous oxide (N2O) is an anesthetic gas with analgesic properties.
- Mouse strain differences in N2O antinociception are significant, with DBA/2 mice being poorly responsive.
- Understanding the genetic basis of N2O responsiveness is crucial for developing targeted pain management strategies.
Purpose of the Study:
- To identify candidate genes influencing antinociceptive responsiveness to nitrous oxide (N2O).
- To investigate the genetic architecture of N2O analgesia using a quantitative trait loci (QTL) approach in a mouse model.
Main Methods:
- Exposure of DBA/2, C57BL/6, B6D2F1, and 22 BXD recombinant inbred (RI) mouse strains to 70% N2O.
- Assessment of antinociception using the acetic acid abdominal constriction test.
- Quantitative trait loci (QTL) analysis of strain means against 1492 mapped marker loci in BXD RI strains.
Main Results:
- C57BL/6 mice showed 78% antinociception, DBA/2 mice showed 22%, and B6D2F1 mice showed 55% response to N2O.
- BXD RI strains clustered into two groups: 16 strains similar to C57BL/6 (61.9-100% response) and six strains similar to DBA/2 (9.1-40% response).
- QTL analysis identified seven chromosomal associations with N2O antinociception, with significant marker loci including Il2ra, Hbb, Hmg1rs7, and Gsl5.
Conclusions:
- Significant genetic variation exists in N2O antinociceptive responsiveness among mouse strains.
- The study successfully mapped quantitative trait loci (QTLs) associated with N2O analgesia, providing a foundation for gene discovery.
- Candidate genes identified may play a role in modulating the effects of N2O on pain perception.