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Regenerations of Spinal Cord Neurons and its Sensory Function in Pathological Pain following Peripheral Nerve Injury

Research Project

Project/Area Number 13470321
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. MEDICINE PROFESSOR, 医学部, 教授 (90034991)

Co-Investigator(Kenkyū-buntansha) TSUKAHARA Masato  YAMAGUCHI UNIV. SCH. MEDICINE PROFESSOR, 医学部, 教授 (20136188)
IBUKI Takae  KYOTO PREF. UNIV. SCH. MEDICINE ASSOC. PROFESSOR, 医学部, 講師 (90232587)
FURUKAWA Shoei  GIFU PHARMAC. COLL. PROFESSOR, 薬学部, 教授 (90159129)
MATSUI Tomohiro  YAMAGUCHI UNIV. SCH. MEDICINE ASSOC. PROFESSOR, 医学部, 助手 (50314828)
OKANO Kozue  YAMAGUCHI UNIV. SCH. MEDICINE ASSOC. PROFESSOR, 医学部, 講師 (50160693)
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥8,100,000 (Direct Cost: ¥8,100,000)
Fiscal Year 2002: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2001: ¥4,700,000 (Direct Cost: ¥4,700,000)
KeywordsNEUROPATHIC PAIN / NEURONAL PLASTICITY / SPINAL GLUTAMATE / C-FOS EXPRESSION / APOPTOSIS / CA ENTRY BLOCKER / NERVE GROWTH FACTOR / 痛み / 脊髄細胞 / グルタメート神経
Research Abstract

The neuronal plasticity of the spinal cord sensory system in pathological pain after peripheral nerve injury has recently recognized as pivotal mechanisms. However, there are no report concerning with combined mechanisms such as regeneration of cellular and functional derangements. The aim of the present study was to investigate the possibility of regeneration of spinal cord neurons of pathological pain using well-established rat model, which is known that the excessive release of glutamate and sP initiate perturbation of intracellular-nucleus processing resulting in increased Ca2+ In addition, we investigated possibilities for treatment resulting from these mechanisms including suppression of afferent input and synthesis of nerve growth factor by magnetic field stimulation. In Rats, the neuropathic pain was produced by legation of left sciatic nerve. Under halothane anesthesia special designed micro dialysis catheter was intrathecally implanted along with PE-10 tube for the spinal glu … More tamate release (HPLC-UV) and drug injection, respectively. For the treatment (1) several kinds of N-type Ca channel blocker (IT), (2) magnetic field stimulation (MFS), or (3) MFS + anti NGF (4) MFS + 4-methyl catechol (4-MC, IP) was respectively administered. After nerve injury, rats showed thermal hyperalgesia accompanied with increased spinal glutamate release during 5-10 days and that was enhanced with time. There were c-foes protein expression and apoptosis of superficial layer of spinal cord during early state of the hyperalgesia followed by the necrosis of the laminate 3-4 (interneuron). Both N-type Ca channel blocker and MFS significantly attenuated spinal glutamate release accompanied with decreased incidences of c-foes, apoptosis and necrosis of spinal cord neurons. In addition, pretreatment of anti NGF with MFS showed less sever of pain facilitation and 4-MC administration, which brings about the synthesis induction of the NGF that it attenuates the spinal glutamate release, and intracellular signaling including c-foes and that, suppresses these histological changes. Based on this study, it is suggested that possible involvement of peripheral nerve growth factors induced by magnetic field stimulation in regeneration of spinal cord neurons and related to attenuation of sensory systems such that of pathological pain. We also reconfirmed that generates modulation in the intracellular - nucleus process, which originates from the excessive excitation of the spinal cord glutamate nerve system and brings about the apoptosis. For the conversion to chronic pain, it was indicated that the dysfunction of the interneuron was concerned, and promotes further understand mechanisms of the nerve - immune network. It 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 N-type Ca channel blocker and magnetic field stimulation. As future direction, it will be needed to establish the transplantation and adeno-vector virus NGF administration for possible treatment for neuropathic pain. Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (41 results)

All Other

All Publications (41 results)

  • [Publications] Marsala J., Ishikawa T., et al.: "Localization and distribution patterns of nicotinamide adenine dinucleotide phosphate diaphoresis exhibiting axons in the white matter of the spinal cord of the rabbit"Cell and Mol Neurobiology. 23. 57-92 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tohyama K, Ishikawa T., et al.: "Role of the pyruvate dehydrogenase complex in rat brain ischemia"Jpn Pharmacology Ther. 31(2). 149-152 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto S., Ishikawa T., et al.: "Intrathecal adenosine A 1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat"Cell and Moll Neurobiology. 23(2). 175-189 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mizuno K., Ishikawa T., et al.: "Differential responses to pial vessels between nitric oxide donor, nitroprusside and trimethaphan in cats"Jpn Pharmacology Ther. 31(2). 141-148 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa T., et al.: "Involvement of increased glutamate release and c-fos expression of spinal cord in developing rat neuropathic pain"Neuroscience. 28. 655-656 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakanishi O., Ishikawa T., et al.: "Involvement of the spinal glutamate release in the inflammatoric and neuropathic pain in rat : modulation by N-type Ca channel blocker"Plasticity of Pain System. 1. 7-8 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa T., et al.: "Characterization of spinal amino acid release and touch-evoked allodynia produced by spinal glycine or GABA receptor antagonist"Neuroscience. 28. 781-786 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yang LC, Ishikawa T. et al.: "Transient spinal cord ischemia in rat : the time course of spinal FOS protein expression and the effect of intraischemic hypothermia"Cell and Moll Neurobiology. 20. 382-394 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohmoto Y, Ishikawa T. et al.: "Changes in local cerebral glucose utilization following radiofrequency-Induced local hyperthermia in the rat-An autoradiographic study"Jan J Hyperthermia Oncology. 17(4). 245-254 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakamoto E., Ishikawa T, et al.: "Evaluation of nerve damage in traumatic trigeminal neuropathy with neurometer"Pain Research. 16. 57-62 (2001)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito H, Furukawa S et al.: "The growth arrest of PC12 cells by nerve growth factor is dependent on phosphatidyl inositol 3-kinase/pathways Akt via p75 neurotrophin receptor"J Neurosci Res. 72. 211-217 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito H, Furukawa S et al.: "Neurotrophins facilitate neuronal differentiation of cultured neural stem cells via induction of mRNA expression of basic helix-loop-helix transcription factors Mash1 and Math1"J Neurosci Res. 71. 648-658 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohmiya M., Furukawa S et al.: "Brain-derived neurotrophic factor alters cell migration of particular progenitor cells in the developing mouse cerebral cortex"Neuroscience Lett. 377. 21-24 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sometani A, Furukawa S et al.: "4 Methylcatechol stimulates phosphorylation of Trk family neurotrophin receptors and neurotrophin receptors and MAP kinases in cultured rat cortical neurons"J Neurosci Res. 198. 63-69 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nitta A, Furukawa S, et al.: "Diabetic neuropathies in brain are induced by deficiency of BDNF"Neurotoxicol Teratol. 24. 695-6701 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa T. et al.: "Spinal Cord Sciences : Neuroplasticity and stem cell treatment in neuropathic pain"Igaku Syoin, Tokyo (in press). (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Marsala J., Ishikawa T., et al: "Localization and distribution patterns of nicotinamide adenine dinucleotide phosphate diaphoresis exhibiting axons in the white matter of the sopinal cord of the rabbit"Cell and Mol Neurobiology. 23(1). 57-92 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Tohyama K, Ishikawa T., et al: "Role of the pyruvate dehydrogenase complex in rat brain ischemia"Jpn Pharmacology Ther. 31(2). 149-152 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yamamoto S., Ishikawa T., et al: "Intrathecal adenosine A 1 receptor agonist attenuates hyperalgesia without inhibiting spinal glutamate release in the rat"Cell and Moll Neurobiology. 23(2). 175-189 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Mizuno K., Ishikawa T., et al: "Differential responses to pial vessels between nitric oxide donor, nitroprusside and trimethaphan in cats"Jpn Pharmacology Ther. 31(2). 141-148 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa T., et al: "Involvement of increased glutamate release and c-fos expression of spinal cord in developing rat neuropathic pain"Neuroscience. 28. 655-656 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakanishi O., Ishikawa T., et al: "Involvement of the spinal glutamate release in the inflammatoric and neuropathic pain in rat : modulation by N-type Ca channel blocker"Plasticity of Pain System. 1. 7-8 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa T., et al: "Characterization of spinal amino acid release and touch-evoked allodynia produced by spinal glycine or GABA receptor antagonist"Neuroscience. 28. 781-786 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Yang LC, Ishikawa T., et al: "Tansient spinal cord ischemia in rat : the time course of spinal FOS protein expression and the effect of intraischemic hypothermia"Cell and Moll Neurobiol. 20. 382-394 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohmoto Y., Ishikawa T., et al: "Changes in local cerebral glucose utilization following radio frequency-Induced local hyperthermia in the rat- An autoradiagraphic study"Jan J Hyperthermic Oncology. 17(4). 245-254 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sakamoto E., Ishikawa T., et al: "Evaluation of nerve damage in traumatic trigeminal neuropathy with neurometer"Pain Research. 16. 57-62 (2001)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito H, Furukawa S et al: "The growth arrest of PC 12 cells by nerve growth factor is dependent on phosphatidylinositol 3-kinase/pathways Akt via p75 neurotrophin receptor"J Neurosci Res. 72. 211-217 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ito H, Furukawa S et al.: "Neurotrophins facilitate neuronal differentiation of cultured neural stem cells via induction of mRNA expression of basic helix-loop-helix transcription actors Mash1 and Math1"J Neurosci Res. 71. 648-658 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ohmiya M, Furukawa S et al.: "Brain-derived neurotrophic factor alters cell migration of particular progenitor cells in the developing mouse cerebral cortex"Neurbscience Lett. 377. 21-24 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Sometani A, Furukawa S et al.: "4 Methylcatechol stimulates phosphorylation of Trk family neurotrophin receptors and neurotrophin receptors and MAP kinases in cultured rat cortical neurons"J Neurosci Res. 198. 63-69 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nitta A, Furukawa S. et al: "Diabetic neuropathies in brain are induced fay deficiency of BDNF"Neurotoxicol Teratol. 24. 695-6701 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Ishikawa T., et al: "Spinal cord sciences : Neuroplasticity and stem cell treatment in neuropathic pain"Igaku Syoin, Tokyo (in press). (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] S.Yamamoto, T.Ishikawa, et al.: "Intrathecal adenosine modulates Nociceptive Response to Formalin Paw Injection Without Inhibiting Spinal Glutamate Release in the Rat"Cell Moll Neurobiol. 23(2). 175-189 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] J.Marsala, T.Ishikawa, et al.: "Localization and distribution patterns of nicotinamide dinucleotide phosphate diaphorase exhibiting axons in the white matter of the spinal cord of the rabbit"Cell Moll Neurobiol. (in press).

    • Related Report
      2002 Annual Research Report
  • [Publications] E.Sakamoto, T.Ishikawa, et al.: "Evaluation of nerve damage in traumatic trigeminal neuropathy with neurometer"Pain Research. 16. 57-62 (2001)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Mizuno, T.Ishikawa, et al.: "Differential Response to Pial Vessels between Nitric Oxide Donor, Nitroprusside and Trimethaphan in Cats"Jpn Pharmacol Ther. 31(2). 141-148 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] K.Tohyama, T.Ishikawa, et al.: "Role of the pyruvate dehydroxygenase complex in rat brain ischemia -determination of survival rates in relation to energy metabolism -"Jpn Pharmacol Ther. 31(2). 149-154 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Ishikawa, M.Nishi, et al.: "Magnetic field stimulation ameliorates neuropatic pain in rats"Pain Resaerach. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] 石川 敏三: "セロトニン:疼痛の発生・維持における脊髄神経可塑性の関与"セロトニン研究会. 45 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] T.Ishikawa: "Spinal glutamate release may evoke thermal hyperalgesia in rats"Soc for Neuroscience(ABSTRACT). 27(印刷中). (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] T.Ishikawa: "Magnetic field stimulation ameliorates neuropatic pain in rats."Pain Resaerach(ABSTRACT). 16(印刷中). (2001)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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