To test the hypo,thasis.that trigeminal pain spdrom,es are complex genetic traits, we recently produced a new mouse model of kraniofacial neuropathic pain (CNP), by unilaterally cutting the infraorbital nerve (IONX). We found thaf pain to light touch (i.e., allodynia) and increased pain to noxious stimuli (i.e., hyperalgesia) appeared in both ears, paws and tail, and depended on the sex and the genetic background of the studied strains. This model is a robust platform to study genetic mechanisms underlying CNP that is seen frequently in humans, especially women.
Our specific aims are to identify candidate genetic factors that contribute to differences in susceptibility to CNP. Since, some of these likely encode voltage- and ligandgated ion channel genes, in AIM-1 we will identify SNPs in 235 such genes across 20 inbred mouse strains and reconstruct their haplotypes.
AIM -2: Phenotyping CNP post-IONX in these mice and a computational genetic analysis of their haplotype map, we will identify genetic factors controlling CNP. Phenoirping 23 AXB-BXA recombinant inbred mouse strains, followed by linkage analysis of their known genetic map will enable us to idenbfy QTL intervals for CNP. Using expression arrays we will identify genes differentially expressed in trigeminal subnucleus caudalis (Vc) of strains contrasting on CNP levels post-IONX. Superposition of these 3 maps should enable candidate genes for CNP to be identified. Not part of this study, we will genotype these genes in cohorts of trigeminal (and other) neuropathic pain patients.
AIM -3: CNP levels in 43 strains typed in AIM 2 will enable us to offer the highest contrasting strains as a standardized new platform to study mechanisms of CNS plasticity after nerve injury, test novel analgesics and produce new hypotheses for indepth future studies. We will phenotype 8 of these strains for traits supposedly correlating CNP and undetlying central plasticity following nerve injury: (i) excitotoxic destruction of pain-suppressing neurons in Vc, (ii) Seizure proneness as a probe of CNS inhibitions, (iii) changes in astro- and microglial cells, and (iv) FOS labeling to study plasticity in somatotic maps of Vc and lumbosacral neuronal pools that respond to acute noxious stimulation in sites of extratenitorial hyperalgesia. These genetic and phenomic studies are proposed as a new and robust model to study trigeminal pain syndromes. Identification of genetic factors affecting trigeminal pain syndromes could provide novel therapeutic targets.

National Institute of Health (NIH)
National Institute of Dental & Craniofacial Research (NIDCR)
Research Project (R01)
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Special Emphasis Panel (ZDE1-YL (41))
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Kusiak, John W
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University of Toronto
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M5 1-S8
Avivi-Arber, Limor; Seltzer, Ze'ev; Friedel, Miriam et al. (2016) Widespread Volumetric Brain Changes following Tooth Loss in Female Mice. Front Neuroanat 10:121