title: Peripherally increased artemin is a key regulator of TRPA1/V1 expression in primary afferent neurons.
abstract: BACKGROUND
  Artemin, a member of the glial cell line-derived neurotrophic factor family, is known to have a variety of neuronal functions, and has been the subject of attention because it has interesting effects, including bi-directional results in modulation in neuropathic and inflammatory pain. It has been shown that the overexpression of artemin is associated with an increase in the expression of TRP family channels in primary afferents and subsequent hyperalgesia, and an increase in neuronal activity. The purpose of this study was to examine the peripheral synthesis of artemin in inflammatory and neuropathic pain models, and to demonstrate the effects of long-term or repeated application of artemin in vivo on pain behaviors and on the expression of TRP family channels. Further, the regulatory mechanisms of artemin on TRPV1/A1 were examined using cultured DRG neurons.
  
  
  RESULTS
  We have demonstrated that artemin is locally elevated in skin over long periods of time, that artemin signals significantly increase in deep layers of the epidermis, and also that it is distributed over a broad area of the dermis. In contrast, NGF showed transient increases after peripheral inflammation. It was confirmed that the co-localization of TRPV1/A1 and GFRα3 was higher than that between TRPV1/A1 and TrkA. In the peripheral sciatic nerve trunk, the synthesis of artemin was found by RT-PCR and in situ hybridization to increase at a site distal to a nerve injury. We demonstrated that in vivo repeated artemin injections into the periphery changed the gene expression of TRPV1/A1 in DRG neurons without affecting GFRα3 expression. Repeated artemin injections also induced mechanical and heat hyperalgesia. Using primary cultured DRG neurons, we found that artemin application significantly increased TRPV1/A1 expression and Ca(2+) influx. Artemin-induced p38 MAPK pathway regulated the TRPV1 channel expression, however TRPA1 upregulation by artemin is not mediated through p38 MAPK.
  
  
  CONCLUSIONS
  These data indicate the important roles of peripherally-derived artemin on the regulation of TRPV1/A1 in DRG neurons in pathological conditions such as inflammatory and neuropathic pain.
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. ymiyagaw@hyo-med.ac.jp.|Department of Anesthesiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. ymiyagaw@hyo-med.ac.jp.
authors.forename: Yasuko
authors.initials: Y
authors.lastname: Ikeda-Miyagawa
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. ki-kobay@hyo-med.ac.jp.
authors.forename: Kimiko
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. yamanaka@hyo-med.ac.jp.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Yamanaka
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. okubo@hyo-med.ac.jp.
authors.forename: Masamichi
authors.initials: M
authors.lastname: Okubo
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, 650-8530, Japan. wangshl@huhs.ac.jp.
authors.forename: Shenglan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacy, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, 650-8530, Japan. ydai@huhs.ac.jp.
authors.forename: Yi
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. h-yagi@hyo-med.ac.jp.
authors.forename: Hideshi
authors.initials: H
authors.lastname: Yagi
authors.affiliation: Department of Anesthesiology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. mhirose@hyo-med.ac.jp.
authors.forename: Munetaka
authors.initials: M
authors.lastname: Hirose
authors.affiliation: Department of Anatomy and Neuroscience, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo, 663-8501, Japan. noguchi@hyo-med.ac.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Noguchi
mesh_terms: D000818:Animals; D005727:Ganglia, Spinal / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009475:Neurons, Afferent / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism; D010146:Pain / Q000378:metabolism*; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000378:metabolism; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000378:metabolism*
chemical_list: C490887:Artn protein, rat; D009419:Nerve Tissue Proteins; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels; D050916:TRPV Cation Channels; C480976:Trpa1 protein, rat; C493922:Trpv1 protein, rat