title: Correlational analysis for identifying genes whose regulation contributes to chronic neuropathic pain.
abstract: BACKGROUND
  Nerve injury-triggered hyperexcitability in primary sensory neurons is considered a major source of chronic neuropathic pain. The hyperexcitability, in turn, is thought to be related to transcriptional switching in afferent cell somata. Analysis using expression microarrays has revealed that many genes are regulated in the dorsal root ganglion (DRG) following axotomy. But which contribute to pain phenotype versus other nerve injury-evoked processes such as nerve regeneration? Using the L5 spinal nerve ligation model of neuropathy we examined differential changes in gene expression in the L5 (and L4) DRGs in five mouse strains with contrasting susceptibility to neuropathic pain. We sought genes for which the degree of regulation correlates with strain-specific pain phenotype.
  
  
  RESULTS
  In an initial experiment six candidate genes previously identified as important in pain physiology were selected for in situ hybridization to DRG sections. Among these, regulation of the Na+ channel alpha subunit Scn11a correlated with levels of spontaneous pain behavior, and regulation of the cool receptor Trpm8 correlated with heat hypersensibility. In a larger scale experiment, mRNA extracted from individual mouse DRGs was processed on Affymetrix whole-genome expression microarrays. Overall, 2552 +/- 477 transcripts were significantly regulated in the axotomized L5DRG 3 days postoperatively. However, in only a small fraction of these was the degree of regulation correlated with pain behavior across strains. Very few genes in the "uninjured" L4DRG showed altered expression (24 +/- 28).
  
  
  CONCLUSIONS
  Correlational analysis based on in situ hybridization provided evidence that differential regulation of Scn11a and Trpm8 contributes to across-strain variability in pain phenotype. This does not, of course, constitute evidence that the others are unrelated to pain. Correlational analysis based on microarray data yielded a larger "look-up table" of genes whose regulation likely contributes to pain variability. While this list is enriched in genes of potential importance for pain physiology, and is relatively free of the bias inherent in the candidate gene approach, additional steps are required to clarify which transcripts on the list are in fact of functional importance.
authors.affiliation: Center for Oral Biology, Novum, Karolinska Institutet, S-141 04 Huddinge, Sweden. Anna-Karin.M.Persson@ki.se
authors.forename: Anna-Karin
authors.initials: AK
authors.lastname: Persson
authors.forename: Mathias
authors.initials: M
authors.lastname: Gebauer
authors.forename: Suzana
authors.initials: S
authors.lastname: Jordan
authors.forename: Christiane
authors.initials: C
authors.lastname: Metz-Weidmann
authors.forename: Anke M
authors.initials: AM
authors.lastname: Schulte
authors.forename: Hans-Christoph
authors.initials: HC
authors.lastname: Schneider
authors.forename: Danping
authors.initials: D
authors.lastname: Ding-Pfennigdorff
authors.forename: Jonas
authors.initials: J
authors.lastname: Thun
authors.forename: Xiao-Jun
authors.initials: XJ
authors.lastname: Xu
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Wiesenfeld-Hallin
authors.forename: Ariel
authors.initials: A
authors.lastname: Darvasi
authors.forename: Kaj
authors.initials: K
authors.lastname: Fried
authors.forename: Marshall
authors.initials: M
authors.lastname: Devor
mesh_terms: D000818:Animals; D005727:Ganglia, Spinal / Q000503:physiopathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D051379:Mice; D062558:NAV1.9 Voltage-Gated Sodium Channel; D009437:Neuralgia / Q000235:genetics*; D009479:Neuropeptides / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis; D015222:Sodium Channels / Q000235:genetics*; D013045:Species Specificity; D050053:TRPM Cation Channels / Q000235:genetics*
chemical_list: D062558:NAV1.9 Voltage-Gated Sodium Channel; D009479:Neuropeptides; D012333:RNA, Messenger; C491885:Scn11a protein, mouse; D015222:Sodium Channels; D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse