Chronic pain of neuropathic or inflammatory origins affects millions of sufferers in the United States for whom current therapies are inadequate. Because genetic factors significantly contribute to variability among individuals in prolonged pain sensitivity and susceptibility, gene mapping these traits will be useful for the determination of novel and predisposing genetic mechanisms in humans. Thus, this proposal will map the genes underlying variable susceptibility to partial nerve-injury induced hypersensitivity that mimics a common cause of neuropathic pain. Of the multiple pain responses to inflammation, only sensitivity to the immediate, spontaneous nociceptive response has been gene mapped. Thus, this proposal will map the genes under- lying prolonged inflammation-induced hypersensitivity. The genetic model of BXD recombinant inbred (Rl) mice will be used to perform quantitative trait locus (QTL) gene mapping of hypersensitivity to identify regions of the genome containing genes variants associated with variability in the traits.
The Specific Aims will test the hypothesis that the genetic mechanisms underlying these traits are distinct from those responsi- ble for all other classes of nociception and hypersensitivity, including all models previously gene mapped.
In Specific Aim 1, QTL gene mapping of mechanical sensitivity before, and of mechanical hypersensitivity (allodynia) after, ligation of the fifth lumbar nerve will be performed by surveying the sensitivity of 45 strains of Rl mice of known genotype. QTL mapping will proceed without further genotyping in this proposal due to the continually expanding publicly available genotype data for these mice.
In Specific Aim 2, QTL mapping will be similarly performed of spontaneous inflammatory nociception and thermal hypersensitivity following subcutaneous injection of melittin, the major algogenic and inflammatory component of honeybee venom. Due to the use of the BXD Rl mice with known, fixed genotype, single genetic mechanisms responsible for variability in the traits will be immediately determined in Specific Aim 3 by covariance analysis with transcript levels in the forebrain and other brain areas and tissues for which data already exist. In addition, sharing of genetic mechanisms between the hypersensitivity traits and previously studied pain traits and non-pain traits will be determined. These data will be used to determine novel genetic mechanisms of chronic neuropathic and inflammatory pain for predisposition assessment and treatment development.
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