Variability between individuals in pain and analgesia phenotypes is often observed in both clinical and experimental settings. The source of this variability has long been attributed to the interplay of environmental and genetic factors, but we have only recently begun identifying these determinants. Experiments comparing isogenic strains of mice have suggested that different pain tests may share a genetic basis; likewise, analgesic magnitude induced by disparate drug classes may be influenced by a common set of genes. / We have presently used a quantitative trait locus mapping strategy to search for genes responsible for variability in analgesic response to five analgesic drugs (the opioids morphine and U50,488, and the non-opioid drugs clonidine, epibatidine, and WIN55,212-2). We first used a B6129PF2 intercross population to map sensitivity to clonidine, morphine, and WIN55,212-2 to a 30 cM region on distal Chromosome 1. In silico and congenic strain mapping techniques allowed us to refine this linkage, as well as generalize it to four of the five drugs and seven mouse strains. Kcnj9 (GIRK3) was identified as a likely candidate gene underlying response to multiple analgesic modalities. We showed that this gene is differentially expressed between C57BL/6 and 129P3 strains in the periaqueductal gray. We also determined that Kcnj9 null mutant mice exhibit attenuated analgesic responses. / We previously mapped nociceptive response to the formalin test to two loci on Chr. 9 and 10 using an AB6F2 cross. Using in silico mapping, we identified several haplotypes near the Atp1b3 gene on Chr. 9 (a subunit of the sodium-potassium pump) that correlated highly with early phase formalin response. We then showed that pharmacological antagonism of the sodium-potassium channel eliminates the strain difference observed between A and C57BL/6 mice, supporting a role for this gene in determining response to formalin. Positional cloning of the Chr. 10 locus, employing recombinant and congenic strains, allowed us to refine the location of the locus to a <3 cM interval. A small number of genes in this region were identified as differentially expressed by microarray analysis, providing a short list of candidate genes for follow-up investigation.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.103009 |
| Date | January 2006 |
| Creators | Smith, Shad Benjamin. |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Department of Psychology.) |
| Rights | © Shad Benjamin Smith, 2006 |
| Relation | alephsysno: 002600215, proquestno: AAINR32241, Theses scanned by UMI/ProQuest. |
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