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Elucidation of Molecular and Neurobiological Mechanism in Pathophysiological Pain following Peripheral Injury

Research Project

Project/Area Number 10470318
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Anesthesiology/Resuscitation studies
Research InstitutionYamaguchi University

Principal Investigator

ISHIKAWA Toshizo  YAMAGUCHI UNIV. SCH. OF ALLIED HEALTH SCI, ASSOC. PROF,, 医療技術短期大学部, 助教授 (90034991)

Co-Investigator(Kenkyū-buntansha) TSUKAHARA Masato  YAMAGUCHI UNIV. SCH. OF ALLIED HEALTH SCI, PROFESSOR, 医療技術短期大学部, 教授 (20136188)
FURUKAWA Syoei  GIFU PHARMAC. COOL. PHARMACOLOGY, PROFESSOR, 薬学部, 教授 (90159129)
坂部 武史  山口大学, 医学部, 教授 (40035225)
中木村 和彦  山口大学, 医学部, 助教授 (50180261)
Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥9,300,000 (Direct Cost: ¥9,300,000)
Fiscal Year 1999: ¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 1998: ¥5,700,000 (Direct Cost: ¥5,700,000)
KeywordsNeuropathic Pain / Neuronal Prasticity / Spinal glutamate / C-fos Expression / Apoptosis / Necrosis of Interneurons / Treatment of Nerve Growth Factor / 神経因性疼痛 / 神経可塑性 / 脊髄グルタメート / c-fos発現 / アポトーシス / 介在ニューロン死 / Neuropathic pain / Central sensitization / Spinal glutamate / Apoptosis / Neurotrophic factor / Cytokines
Research Abstract

In pathological pain after peripheral nerve injury, the neuronal plasticity of the somatosensory system is recently thought to be directly involved. However, there are few report concerning with molecular and neurobiological mechanisms. The aimof the present study was to elucidate the molecular mechanism of pathological pain using well-established rat model, which may initiate perturbation of intracellular-nucleus processing resulting in increased Ca2+ caused by excessive release of glutamate and sP. In addition, it was to investigate possibilities for treatment resulting from these mechanisms including suppression of afferent input and synthesis of nerve growth factor.
Using rats the left sciatic nerve was ligated to induce the neuropathic pain. Under anesthesia loop-type microdialysis catheter was intrathecally implanted along with PE-10 tube for the spinal glutamate release (HPLC) and drug injection, respactively. For the treatment either (1) N-type Ca channel blocker (I.T.), (2) 5-H … More T2A blocker (I.P.), or (3) 4-methyl cathechol (4-MC, I.P.) was respectively administered.
After sciatic nerve ligation, rats showed thermal hyperalgesia accompanied with increased spinal glutamate release and that was enhanced with time. There were c-fos protein induction and apoptosis of spinal cord neurons in the initial state of the hyperalgesia followed by the necrosis of the interneurons. N-type Ca channel blocker and 5-HT2A receptor antagonist significantly attenuates spinal glutamate release accompanied with decreased incidences of apoptosis and necrosis of interneurons at spinal cord. In addition, 4-MC administration, which brings about the synthesis induction of the nerve growth factor that it, attenuates the spinal glutamate release and that suppresses these histological changes.
Based on the present study, it is suggested that it generates modulation in the intrellular-nucleus process, which originates from the excessive excitation of the spinal cord glutamate nerve system and brings about the apoptosis, and that this is concerned in the manifestation in neuripathic pain. In addition, for the con version to chronic pain, it was indicated that the dysfunction of the interneuron was concerned, and promotes further understand mechanisms of the nerve - immuno network. In proves application of these treatments to the functional recovery in the clinical situation that the induction of the nerve growth factor restores the process for cell death in addition to the usefulness of peripheral 5-HT2A blocker and intrathecal N-type Ca channel blocker. In the future, it will be needed to examine whether transplantation and adeno-vector virus NGF administration are significant treatment for neuropathic pain. Less

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (19 results)

All Other

All Publications (19 results)

  • [Publications] Ishikawa T.et al.: "Characterizntion of spinal ammo acid release and Touch-evoked allodynia produced by spinal giycine or GABAA receptor antagonist"Neurosci. 95(3). 781-786 (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishikawa T.et al.: "Synetgic durg effects on tactile allodynja by GABAA receptor antagonist"Soc.for Neurosci. 25. 934 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishikawa T.et al.: "Transient spinal cord ischemia in rats:the time course of sphal FOS protein expression and the effect of intraischemic hypothermia"Cell Moll Neurobiol. (in press). (2000)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishikawa T.et al.: "Development of apoptosis of spinal cord neurons in rat neuropathic pain"Pain Research. 14. 81-87 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishikawa T.et al.: "Nerve growth factor inducer,4-methyl catechol,potentiatcs central sensitization associatcl with acceleation of spinal glutamate release after mustard oil paw injection in rats"Cell Moll Neurobiol. 19(5). 587-596 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishikawa T.et al.: "Modulation of formain-evoked hyperalgesia intrathecal N-type Ca channel and protein Kinase C inhibitor in the rat"Cell Moll Neurobiol.

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ISHIKAWA, T. et al: "Characterization of spinal amino acid release and Touch-evoked allodynia produced by spinal glycine or GABAA receptor antagonist"Neurosci. 95(3). 781-786 (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ISHIKAWA, T. et al: "Synergic drug effects on tactile allodynia by GABAA receptor antagonist"Soc. for Neurosci. 25. 934 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ISHIKAWA, T. et al: "Transient spinal cord ischemia in rats : the time course of spinal FOS protein expression and the effect of intraischemic hypothermia (27℃)"Cell Moll Neurobiol. (in press). (2000)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ISHIKAWA, T. et al: "Development of apoptosis of spinal cord neurons in rat neuropathic pain"Pain Research. 14. 81-87 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ISHIKAWA, T. et al: "Nerve growth factor inducer, 4-methyl catechol, potentiates central sensitization associated with acceleration of spinal glutamate release after mustard oil paw injection in rats"Cell Moll Neurobiol. 19(5). 587-596 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] ISHIKAWA, T. et al: "Modulation of formalin-evoked hyperalgesia by intrathecal N-type Ca channel and protein Kinase C inhibitor in the rat"Cell Moll Neurobiol. 19(2). 191-197 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] Ishikawa T.: "Characterization of spinal amino acid release and Touch-evoked allodynia produced by spinalglycine or GABAA receptor antasonist"Neuroscience. 95・3. 781-786 (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishikawa T.: "Synergic drug effects on tactile allodynia by GABAA receptor antagonist"Soc. For Neuroscience. 25. 934 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishikawa T.: "Transient spinal cord ischemia in rats: the time course of spinal FOS protein expression and effect of intraischemic hypothemia"Cell Moll Neurobiol. (in press). (2000)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishikawa T.: "Development of apoptosis of spinal cord neurons in rat neuropathic pain"Soc. For Neuroscience. 25. 1442 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Ishikawa T,et al.: "Characterization of spinal amino acid release and touch-evoked allodynia produced by spinal glycine or GABA-A receptor antagonist" Neurosci. (in press).

    • Related Report
      1998 Annual Research Report
  • [Publications] 石川敏三: "痛覚過敏症における神経成長因子の関与" 薬理と治療. 26・6. 245-250 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] 石川敏三,他: "ラット坐骨神経絞扼後の痛覚過敏と脊髄細胞のアポトーシス発現" Pain Res. (in press).

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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