title: Function and postnatal changes of dural afferent fibers expressing TRPM8 channels.
abstract: BACKGROUND
  Genome-wide association studies have identified TRPM8 (transient receptor potential melastatin 8) as one of the susceptibility genes for common migraine. Here, we investigated the postnatal changes of TRPM8-expressing dural afferent fibers as well as the function of dural TRPM8 channels in mice.
  
  
  RESULTS
  First, we quantified the density and the number of axonal branches of TRPM8-expressing fibers in the dura of mice expressing farnesylated enhanced green fluorescent protein (EGFPf) from one TRPM8 allele between postnatal day 2 (P2) to adulthood. The number of axonal branches on individual dural EGFP-positive fibers was decreased by 30% between P2 and P11. The density of dural EGFP-positive fibers was subsequently reduced by 50% between P16 and P21. Conversely, the density and the number of branches of axons expressing calcitonin gene-related peptide remained stable in postnatal mouse dura. The density of TRPM8-expressing fibers innervating the mouse cornea epithelium was significantly increased from P2 to adulthood. Next, we tested the function of dural TRPM8 channels in adult mice and found that TRPM8 agonist menthol effectively inhibited the nocifensive behavior evoked by dural application of inflammatory mediators.
  
  
  CONCLUSIONS
  Our results indicate that the TRPM8-expressing dural afferent fibers undergo cell- and target tissue-specific axonal pruning during postnatal development. Activation of dural TRPM8 channels decreases meningeal irritation-evoked nocifensive behavior in adult mice. This provides a framework to further explore the role of postnatal changes of TRPM8-expressing dural afferents in the pathophysiology of pediatric and adult migraine.
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. renl@anest.wustl.edu.
authors.forename: Lynn
authors.initials: L
authors.lastname: Ren
authors.affiliation: Department of Biological Structure, Neurobiology and Behavior Graduate Program, University of Washington, Seattle, WA, 98195, USA. dhaka@uw.edu.
authors.forename: Ajay
authors.initials: A
authors.lastname: Dhaka
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO, 63110, USA. caoy@anest.wustl.edu.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Cao
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D001522:Behavior, Animal; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D004388:Dura Mater / Q000187:drug effects / Q000378:metabolism*; D019573:Epithelium, Corneal / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008610:Menthol / Q000494:pharmacology; D051379:Mice; D009475:Neurons, Afferent / Q000187:drug effects / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000819:agonists / Q000378:metabolism*
chemical_list: D050053:TRPM Cation Channels; C492297:TRPM8 protein, mouse; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D008610:Menthol; D015740:Calcitonin Gene-Related Peptide