Genetics of individual variability in pain and analgesia; interactions between stress and pain systems.
Marked variability is observed in clinical pain reports and in sensitivity to experimental stimuli in people and animals. Genetic factors significantly contribute to this variability, but we are only in the initial stages of identifying the responsible genetic mechanisms. In my lab, we are currently using rodent strain differences to study genomic covariance with sensitivity to a number of genetically fundamental types of pain. These include spontaneous pain behaviors due to inflammation and the subsequent prolonged hypersensitivity that is of greater relevance to clinical pain than the vast majority of experimental pain traits mapped so far. The methods we use include genetic correlation analysis with standard inbred strains of mice and whole-genome quantitative trait locus (QTL) genetic mapping of recombinant inbred mice. Biostatistical analyses of archival genomic, phenomic and transcriptomic data are then performed to expand the analysis to a systems genetics level. These methods are complemented by candidate gene testing with neuropharmacological and other studies to determine the responsible genes underlying the pain traits, including stress-induced endogenous pain suppression. This research will identify novel genes involved in the traits and provide novel therapeutic targets.
A second area of interest is in the interactions between stress and pain systems that modulate pain sensitivity and may lead to increased susceptibility to chronic pain. Although acute stress usually decreases pain sensitivity, prolonged stress is considered to lead to increased pain sensitivity and greater susceptibility to chronic pain. We are currently concentrating on the effects of corticotropin-releasing factor (CRF) receptor ligands, knockout of CRF receptor subtypes, and on the specificity and mechanisms of the effects of hypophysectomy, which can dramatically alter pain sensitivity in rodents and in advanced cancer pain patients.
Philip, V.M., Duvvuru, S., Gomero, B., Ansah, T.A., Blaha, C.D., Cook, M.N., Hamre, K.M., Lariviere, W.R., Matthews, D.B., Mittleman, G., Goldowitz, D., Chesler, E.J. High-throughput behavioral phenotyping in the expanded panel of BXD recombinant inbred strains. Genes, Brain and Behavior (in press).
Lariviere, W.R. Genetics of neuropathic pain. In: Dobretsov, M. and Zhang, J.M., (Eds.), Mechanisms of Pain in Peripheral Neuropathy. Trivandrum, India: Research Signpost, 2009.
Lariviere, W.R., Sattar, M.A. and Melzack, R. Inflammation-susceptible Lewis rats demonstrate less sensitivity than resistant Fischer rats in the formalin inflammatory pain test and with repeated thermal tail flick testing. Journal of Neurophysiology 95, 2889-2897, 2006.
Lariviere, W.R., McBurney, D.H., Frot, M. and Balaban, C.D. Tonic, phasic and integrator components of psychophysical responses to topical capsaicin account for differences of location and sex. The Journal of Pain 6, 777-781, 2005.
Lariviere, W.R., Wilson, S.G., McLaughlin, T.M., Kokayeff, A., West, E.E., Adhikari, S.M., Wan,Y. and Mogil, J.S. Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain 97, 75-86, 2002.
Lariviere, W.R., Chesler, E.J. and Mogil, J.S. Transgenic studies of pain and analgesia: mutation or background genotype? The Journal of Pharmacology and Experimental Therapeutics 297, 467-473, 2001.
Lariviere, W.R., Melzack, R. The role of corticotropin-releasing factor in pain and analgesia. Pain 84, 1-12, 2000.