It has been demonstrated that there exists variability in pain sensitivity that can be accounted for by genetic factors, but also that the pain sensitivity of any genotype on one nociceptive assay is statistically independent of sensitivity on a nociceptive assay of a different modality. For example, knowing that an inbred mouse strain is very sensitive to chemical nociception does not predict sensitivity on thermal or mechanical nociceptive assays. Learning what genes underlie sensitivity to these three modalities of pain as separate entities may enlighten us as to how these modalities are differentially processed in the nervous system. If these pain-related genes and their protein products are amenable to pharmacological alteration, this could lead to direct strategies for the development of novel analgesics.
The aim of this proposal is to use quantitative trait locus (QTL) mapping techniques to find the chromosomal regions containing genes responsible for variability in nociceptive sensitivity to each of the three major pain modalities: chemical, thermal and mechanical. This will be accomplished by testing the 2nd filial (F2) generation of a cross between the least and most sensitive inbred strains on three common murine nociceptive assays: the formalin test, the Hargreaves' test of thermal nociception, and the von Frey fiber test of mechanical sensitivity. The inheritance of nociceptive sensitivity in these three sets of F2 mice will then be correlated with the inheritance of polymorphic DNA markers (microsatellites) of known chromosomal location. Regions of high correlation reveal genomic loci containing genes responsible for the original strain differences. In future work, candidate gene approaches or positional cloning will identify these genes.
