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Development of new therapeutics for pain, based on the suppression of tyrosine kinase activity

Research Project

Project/Area Number 16591554
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionKyoto Prefectural University of Medicine

Principal Investigator

HIROSE Munetaka  Kyoto Prefectural University of Medicine, Anesthesiology, Instructor, 医学研究科, 助手 (50275228)

Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2004: ¥1,700,000 (Direct Cost: ¥1,700,000)
KeywordsTyrosine kinase / Local anesthetic / Nerve growth factor / TrkA / Lidocaine / Hyperalgesia / Autophosphorylation / PC12
Research Abstract

TrkA and TrkB, which are the receptors of nerve growth factor(NGF) produced in the peripheral tissue and brain-derived neurotrophic factor(BDNF) as a neurotransmitter, reportedly plays a pivotal role for development of pain. NGF binding to extracellular portion of TrkA leads to autophosphorylation of five different tyrosine residues, located in the juxamembrane domain (Y490), in the activation loop of tyrosine kinase domain (Y670, Y674, Y675), and in the C-terminal (Y785). Amino acid sequences of activation loop including these three tyrosine residues (Y670, Y674, Y675) in TrkA reveal homology with those of the insulin receptor, which are the target of the inhibitory effect of lidocaine on the insulin receptor tyrosine kinase activity. I hypothesized that local anesthetics inhibit NGF-stimulated tyrosine kinase activity of TrkA and suppress NGF signaling. The present study investigated the effect of local anesthetics, lidocaine, bupivacaine, and procaine (40 μM, 400 μM and 4000 μM), on NGF signaling using PC 12 cell line derived from rat pheochoromocytoma, which is a useful model for studying NGF signaling and sympathetic sprouting.
Both 400 μM and 4000 μM of lidocaine significantly attenuated NGF-stimulated tyrosine phosphorylation of TrkA in PC 12 cells and also suppressed the increase of neurite bearing cells stimulated by NGF. Over 40 μM of bupivacaine and 4000 μM of procaine suppressed both NGF-stimulated tyrosine phosphorylation of TrkA and the increase of neurite bearing cells stimulated by NGF. Only 4000 μM of lidocaine and bupivacaine had cytotoxic effect on PC 12 cells. idocaine (400 μM) corresponds to the concentration around or in the peripheral nerve after local administration. The inhibition of TrkA activity might be involved in the mechanism of the suppression of chronic pain by local anesthetics.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (11 results)

All 2006 2005 2004

All Journal Article (10 results) Book (1 results)

  • [Journal Article] Local anesthetics suppress nerve growth factor-mediated neurite outgrowth by inhibition of tyrosine kinase activity of TrkA.2006

    • Author(s)
      Takatori M, Kuroda Y, Hirose M
    • Journal Title

      Anesthesia and Analgesia 102

      Pages: 462-467

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibition of autophosphorylation of epidermal growth factor receptor by small peptides in vitro.2006

    • Author(s)
      Abe M, Kuroda Y, Hirose M, Watanabe Y, Nakano M, Handa T
    • Journal Title

      British Journal of Pharmaology 印刷中

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor.2006

    • Author(s)
      Sakaguchi M, Kuroda Y, Hirose M
    • Journal Title

      Anesthesia and Analgesia 印刷中

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Inhibition of autophosphorylation of epidermal growth factor receptor by small peptides in vitro.2006

    • Author(s)
      Abe M, Kuroda Y, Hirose M, Watanabe Y, Nakano M, Handa T
    • Journal Title

      British Journal of Pharmaology (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor.2006

    • Author(s)
      Sakaguchi M, Kuroda Y, Hirose M
    • Journal Title

      Anesthesia and Analgesia (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Local anesthetics suppress nerve growth factor-mediated neurite outgrowth by inhibition of tyrosine kinase activity of TrkA2006

    • Author(s)
      Takatori M, Kuroda Y, Hirose M
    • Journal Title

      Anesthesia and Analgesia 102

      Pages: 462-467

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Inhibition of autophosphorylation of epidermal growth factor receptor by small peptides in vitro.2006

    • Author(s)
      Abe M, Kuroda Y, Hirose M, Watanabe Y, Nakano M, Handa T
    • Journal Title

      British Journal of Pharmaology (印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Antiproliferative effect of lidocaine on human tongue cancer cells with inhibition of the activity of epidermal growth factor receptor.2006

    • Author(s)
      Sakaguchi M, Kuroda Y, Hirose M
    • Journal Title

      Anesthesia and Analgesia (印刷中)

    • Related Report
      2005 Annual Research Report
  • [Journal Article] 鏡視下手術の術後鎮痛2005

    • Author(s)
      廣瀬宗孝
    • Journal Title

      ペインクリニック 26

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Annual Research Report 2005 Final Research Report Summary
  • [Journal Article] NSAIDを用いた治療の新展開2004

    • Author(s)
      廣瀬宗孝, 細川豊史
    • Journal Title

      医学のあゆみ 211

      Pages: 527-530

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] 麻酔看護シミュレーション2004

    • Author(s)
      廣瀬宗孝
    • Total Pages
      120
    • Publisher
      メデイカ出版
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary

URL: 

Published: 2004-04-01   Modified: 2016-04-21  

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