Pain is a tremendous human health problem, representing the primary symptom that motivates people to seek medical attention and accounting for considerable morbidity and even mortality. The expression of pain us subject to large individual difference; even after presumable similar injuries some people report pain whereas others are pain-free. In addition, responses to analgesic (i.e., pain-inhibiting) drugs are quite variable. Accordingly, a number of genetic animal models of analgesic sensitivity have been identified or developed, and much is now known about the genetic mediation of analgesic sensitivity, including the location of genes influencing this trait. In contrast, almost nothing is known about a related and conceptually more basic issue, the genetic mediation of sensitivity to pain itself. To full understand the mechanism of action of analgesic drugs, one must first understand mechanisms underlying pain transmission and modulation. We have identified two inbred mouse strains that are highly sensitive to, and highly resistant to, pain as measured on a number of standard assays. The most robust stain difference is seen on the """"""""tonic phase""""""""of the formalin test, an assay of inflammatory pain that has received considerable attention in recent years. The present proposal has two main aims. First, we will endeavor to localize chromosomal regions containing genes that are associated with variability in pain sensitivity, using a technique known as quantitative trait locus (QTL) mapping. Due to the extensive linkage homology that exists between the mouse and human genomes, mapped QTLs in the mouse are likely to immediately suggest chromosomal regions for QTLs in humans. The second major aim of this proposal is to use artificial selection to produce mice displaying high and low tonic phase formalin pain behavior. Such seletected mouse lines would represent the first direct genetic model of pain sensitivity. We will use these selected lines to assess possible genetic correlations with opioid analgesic magnitude, non-opioid analgesic magnitude, sensitivity to inflammation-induced hyperalgesia, and susceptibility to neuropathic pain. Possible clinical applications of this work might include the development of a pre-operative blood test that would predict post-operative analgesic requirements, the development of novel analgesic strategies, and gene therapy for chronic pain sufferers refractory to conventional treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DA011394-03
Application #
2898199
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Thomas, David Dale
Project Start
1997-09-30
Project End
2002-07-31
Budget Start
1999-08-01
Budget End
2000-07-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Psychology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
Sorge, Robert E; LaCroix-Fralish, Michael L; Tuttle, Alexander H et al. (2011) Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci 31:15450-4
Wilson, Sonya G; Bryant, Camron D; Lariviere, William R et al. (2003) The heritability of antinociception II: pharmacogenetic mediation of three over-the-counter analgesics in mice. J Pharmacol Exp Ther 305:755-64
Wilson, Sonya G; Smith, Shad B; Chesler, Elissa J et al. (2003) The heritability of antinociception: common pharmacogenetic mediation of five neurochemically distinct analgesics. J Pharmacol Exp Ther 304:547-59
Bon, Karine; Lichtensteiger, Carol A; Wilson, Sonya G et al. (2003) Characterization of cyclophosphamide cystitis, a model of visceral and referred pain, in the mouse: species and strain differences. J Urol 170:1008-12
Lariviere, William R; Wilson, Sonya G; Laughlin, Tinna M et al. (2002) Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain 97:75-86
Chesler, Elissa J; Wilson, Sonya G; Lariviere, William R et al. (2002) Identification and ranking of genetic and laboratory environment factors influencing a behavioral trait, thermal nociception, via computational analysis of a large data archive. Neurosci Biobehav Rev 26:907-23
Wilson, Sonya G; Chesler, Elissa J; Hain, Heather et al. (2002) Identification of quantitative trait loci for chemical/inflammatory nociception in mice. Pain 96:385-91
Lariviere, W R; Chesler, E J; Mogil, J S (2001) Transgenic studies of pain and analgesia: mutation or background genotype? J Pharmacol Exp Ther 297:467-73
Mogil, J S; Pasternak, G W (2001) The molecular and behavioral pharmacology of the orphanin FQ/nociceptin peptide and receptor family. Pharmacol Rev 53:381-415
Wan, Y; Wilson, S G; Han, J et al. (2001) The effect of genotype on sensitivity to electroacupuncture analgesia. Pain 91:5-13

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