title: Wound-healing growth factor, basic FGF, induces Erk1/2-dependent mechanical hyperalgesia.
abstract: Growth factors such as nerve growth factor and glial cell line-derived neurotrophic factor are known to induce pain sensitization. However, a plethora of other growth factors is released during inflammation and tissue regeneration, and many of them are essential for wound healing. Which wound-healing factors also alter the sensitivity of nociceptive neurons is not well known. We studied the wound-healing factor, basic fibroblast growth factor (bFGF), for its role in pain sensitization. Reverse transcription polymerase chain reaction showed that the receptor of bFGF, FGFR1, is expressed in lumbar rat dorsal root ganglia (DRG). We demonstrated presence of FGFR1 protein in DRG neurons by a recently introduced quantitative automated immunofluorescent microscopic technique. FGFR1 was expressed in all lumbar DRG neurons as quantified by mixture modeling. Corroborating the mRNA and protein expression data, bFGF induced Erk1/2 phosphorylation in nociceptive neurons, which could be blocked by inhibition of FGF receptors. Furthermore, bFGF activated Erk1/2 in a dose- and time-dependent manner. Using single-cell electrophysiological recordings, we found that bFGF treatment of DRG neurons increased the current-density of NaV1.8 channels. Erk1/2 inhibitors abrogated this increase. Importantly, intradermal injection of bFGF in rats induced Erk1/2-dependent mechanical hyperalgesia.
  
  
  CONCLUSIONS
  Analyzing intracellular signaling dynamics in nociceptive neurons has proven to be a powerful approach to identify novel modulators of pain. In addition to describing a new sensitizing factor, our findings indicate the potential to investigate wound-healing factors for their role in nociception.
authors.affiliation: Max Planck Institute for Molecular Genetics, Berlin, Germany Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany Institute for Systems Theory and Automatic Control, University of Stuttgart, Stuttgart, Germany Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Germany Department of Neurology, Yale University School of Medicine, New Haven, CT, USA Center for Neuroscience and Regeneration Research, New Haven, CT, USA Division of Neuroscience, Departments of Medicine and Oral & Maxillofacial Surgery, University of California, San Francisco, CA, USA Klinik für Anästhesiologie und Operative Intensivmedizin, Experimentelle Anästhesiologie und Schmerzforschung, Uniklinik Köln, Köln, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Andres
authors.forename: Jan
authors.initials: J
authors.lastname: Hasenauer
authors.forename: Hye-Sook
authors.initials: HS
authors.lastname: Ahn
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Joseph
authors.forename: Jörg
authors.initials: J
authors.lastname: Isensee
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.forename: Frank
authors.initials: F
authors.lastname: Allgöwer
authors.forename: Jon D
authors.initials: JD
authors.lastname: Levine
authors.forename: Sulayman D
authors.initials: SD
authors.lastname: Dib-Hajj
authors.forename: Stephen G
authors.initials: SG
authors.lastname: Waxman
authors.forename: Tim
authors.initials: T
authors.lastname: Hucho
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D016222:Fibroblast Growth Factor 2 / Q000633:toxicity*; D005727:Ganglia, Spinal / Q000187:drug effects / Q000503:physiopathology*; D006930:Hyperalgesia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000096:biosynthesis; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*
chemical_list: D016222:Fibroblast Growth Factor 2; C496350:Fgfr1 protein, rat; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: Erk1/2; FGF-2; FGF-β; Inflammatory pain; MAP kinase; Na(V)1.8; Nociception; Pain; Peripheral sensory neuron; Quantitative automated microscopy; Randall Selitto; Sensitization signaling; Voltage gated sodium channels; Wound healing; bFGF