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

Research Project

Project/Area Number 15390475
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) FURUKAWA Shoei  GIFU PHARMAC.COLL., PROFESSOR, 薬学部, 教授 (90159129)
IBUKI Takae  KYOTO PREF.UNIV., SCH.MEDICINE, ASSIS. PROFESSOR, 大学院, 講師 (90232587)
TSUKAHARA Masato  YAMAGUCHI UNIV., SCH.MEDICINE, PROFESSOR, 医学部, 教授 (20136188)
OKANO Kozue  YAMAGUCHI UNIV., SCH.MEDICINE, ASSOC. PROFESSOR, 医学部, 助教授 (50160693)
MATSUI Tomohiro  YAMAGUCHI UNIV., SCH.MEDICINE, RES.ASSOSIATE, 医学部, 助手 (50314828)
櫻井 雅浩  東北大学, 大学院・胸部外科, 助手 (80344654)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 2003: ¥4,500,000 (Direct Cost: ¥4,500,000)
KeywordsNEUTROPATHIC PAIN / NEURONAL PLASTICITY / SPINAL GLUTAMATE / C-FOS EXPRESSION / APOPTOSIS / Ca ENTRY BLOCKER / NERVE GROWTH FACTOR
Research Abstract

The neuronal regeneration of the peripheral-spinal cord sensory system in pathological pain after peripheral nerve injury has recently focused. However, there are no report concerning with either bone marrow stromal cell (BMSc) transplantation or trophic factor treatment for regeneration of cellular and functional derangements. We investigated 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 by BMSc transplantation into spinal cord and synthesis of nerve growth factor by 4 methyl cathechol amine (4-MC).
The rats were divided into following two studies, BMSc and 4-MC study, respectively. In BMSc study, rats were subjected to spinal cord injury by completion and touch-evoked allodynia combined with astrocyte growing after BMSc … More implantation (cultured neruspheas). In 4-MC study, the neuropathic pain was produced by legation of left sciatic nerve. The pain response (thermal hyperalgesia) combined with c-fos expression, apoptosis (TUNEL), and GFAP (astrocyte) at spinal cord were measured after nerve injury. For the treatment, (1) 4-MC, (2) magnetic field stimulation (MFS), (3) N-type Ca entry blocker, combined with anti-NGF, was respectively administered.
After transplantation of intrathecal BMSc one fourth of rats can gait and pain sensation was improved. In these improved animals, astrocyte growing was evident at both ventral and dorsal horn of spinal cord. On the other hands, after sciatic 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). In decreased pain sensation animals appeared astrocyte growing at around Rexed III where is selectively damaged neurons after nerve injury. 4-MC significantly improved neuropathic pain associated with decreased incidences of c-foes, apoptosis, necrosis, and GFAP immunoreactivity of spinal cord neurons. 4-MC administration, which brings about the synthesis induction of the Brain derivated trophic factor and NGF that it attenuates the spinal glutamate release, and intracellular signaling including c-foes and that, suppresses these histopathological changes.
Based on present study, we demonstrated that possible improvement of pain sensation by peripheral nerve injury by injecting BMSc and trophic factor. In these functional recovery, the regeneration of neuron and astrocytes in Rexed III of spinal cord where is known as velnerable region and causes pain facilitation as disinhibitiom mechanisms. Otherwise, the 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. 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 bone marrow stromal cells and trophic factor treatments to the functional recovery in the clinical situation As future direction, it will be needed to confirm safety of transplantation for possible treatment for neuropathic pain. Less

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (48 results)

All 2005 2004 2003 Other

All Journal Article (40 results) Book (1 results) Publications (7 results)

  • [Journal Article] P38 MAPK and iNOS are involved in LPS-induced PGE2 release from spinal microglia2005

    • Author(s)
      T.Matsui, T.Ishikawa, et al.
    • Journal Title

      Society for Neuroscience

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] NEUROTROPHINE INDUCER, 4-METHYL CATHECHOL IMPROVES RAT NEUROPATHIC PAIN ASSOCIATED WITH ENHANCEMENT OF GFAP-IMMUNOREACTIVITY IN SPINAL CORD2005

    • Author(s)
      T.Ishikawa, M.Nishi, et al.
    • Journal Title

      Society for Neuroscience

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A Novel Ca Channel blocker, Cilinidipine, Inhibits Formalin-evoked Pain Responses in Relation to Spinal Glutamate Release in Rats2005

    • Author(s)
      Y.Matsumoto, T.Ishikawa, et al.
    • Journal Title

      Neurosci Lets (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] 痛覚過敏症における多様性分子機構2005

    • Author(s)
      石川 敏三, 松井 智浩
    • Journal Title

      第10回セロトニン研究会論文集

      Pages: 1-3

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Inflammation-induced GDNF improves locomotor function after spinal cord injury2005

    • Author(s)
      Hashimoto M, Furukawa S, et al.
    • Journal Title

      Neuro Report 16

      Pages: 99-102

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages2005

    • Author(s)
      Hashimoto M, Furukawa S, et al.
    • Journal Title

      79

      Pages: 476-487

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] P38 MAPK and iNOS are involved in LPS-induced PGE2 release from spinal microglia.2005

    • Author(s)
      T.Matsui, T.Ishikawa, et al.
    • Journal Title

      Society for Neuroscience

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] NEUROTROPHINE INDUCER, 4-METHYL CATHECHOL IMPROVES RAT NEUROPATHIC PAIN ASSOCIATED WITH ENHANCEMENT OF GFAP-IMMUNOREACTIVITY IN SPINAL CORD.2005

    • Author(s)
      T.Ishikawa, M.Nishi, et al.
    • Journal Title

      Society for Neuroscience

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inflammation-induced GDNF improves locomotor function after spinal cord injury.2005

    • Author(s)
      Hashimoto M, Furukawa S, et al.
    • Journal Title

      Neuro Report 16

      Pages: 99-102

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages.2005

    • Author(s)
      Hashimoto M, Furukawa S, et al.
    • Journal Title

      J Neurosci Res 79

      Pages: 476-487

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Involvement of glial cell line-derived neurotrophic factor in activation processes of rodent macrophages2005

    • Author(s)
      Hashimoto M, Furukawa S, et al.
    • Journal Title

      J Neurosci Res 79

      Pages: 476-487

    • Related Report
      2004 Annual Research Report
  • [Journal Article] TRANSPLANTATION OF BONE MARROW STROMAL CELLS COMBINED WITH NESTIN POSITIVE CELLS ONTO INJURED SPINAL CORD : SIGNIFICANT RECOVERY OF MOTOR FUNCTION AND ELECTROPHYSIOLGICAL EVALUTION2004

    • Author(s)
      H.Suzuki, T.Ishikawa, et al.
    • Journal Title

      Neuroscience

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Biochemical and physical treatment in rat neuropathic pain and nerve growth factor2004

    • Author(s)
      M.Nishi, T.Ishikawa, et al.
    • Journal Title

      PAIN RESEARCH 19.4

      Pages: 141-149

    • NAID

      10013596382

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] INVOLVEMENT OF NERVE GROWTH FACTOR IN RAT NEUROPATHIC PAIN2004

    • Author(s)
      O.Nakanishi, T.Ishikawa, et al.
    • Journal Title

      Neuroscience

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] INFLAMMATORY MEDIATOR, 5HT DOES NOT INFLUENCE NGF-RELATED HYPERALGESIA IN RATS2004

    • Author(s)
      T.Ishikawa, Y.Matsumoto, et al.
    • Journal Title

      Neuroscience

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Hydrophobic dipeptide, Leu-Ile, protects against neuronal death by inducing BDNF and GDNF synthesis2004

    • Author(s)
      Nitta A, Furukawa S, et al.
    • Journal Title

      J Neurosci Res 78

      Pages: 250-258

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Axonal regrowth downregulates the synthesis of glial cell line-derived neurotrophic factor in the lesioned rat sciatic nerve2004

    • Author(s)
      Yamada Y, Furukawa S, et al.
    • Journal Title

      J Neuro Lett 364

      Pages: 11-15

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mild hypothermia inhibits IL-10 production in peripheral blood Mononuclear cells2004

    • Author(s)
      Matsui T, Ishikawa T, et al.
    • Journal Title

      Acta Anaesthesiol.Scand. 48

      Pages: 205-210

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Magnetic Field Stimulation Improves Rat Neuropathic Pain : Possible Involvement of Nerve Growth Factor2004

    • Author(s)
      T Ishikawa, M Nishi, et al.
    • Journal Title

      The 2nd Asian Pain Symposium (proceeding)

      Pages: 54-54

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inflammatory Mediator, Noradrenaline Possibly Influence NGF-related Hyperalgesia in Rats2004

    • Author(s)
      K Yamaguchi, T Ishikawa, et al.
    • Journal Title

      The 2nd Asian Pain Symposium (proceeding)

      Pages: 56-56

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] COX-1 and COX-2 Dependent Release of PGE2 from LPS-activated Spinal Microglia2004

    • Author(s)
      T Matsui, T Ishikawa, et al.
    • Journal Title

      The 2nd Asian Pain Symposium (proceeding)

      Pages: 64-64

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] International Symposium on Spinal Cord Sciences ; Neuroplasticity and stem cell treatment in spinal cord2004

    • Author(s)
      Ishikawa T., Takano Y., et al.
    • Journal Title

      Jan J Clin Anesth Vol.24(1)

      Pages: 31-72

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] TRANSPLANTATION OF BONE MARROW STROMAL CELLS COMBINED WITH NESTINPOSITIVE CELLS ONTO INJURED SPINAL CORD : SIGNIFICANT RECOVERY OF MOTOR FUNCTION AND ELECTROPHYSIOLOGICAL EVALUTION.2004

    • Author(s)
      H.Suzuki, T.Ishikawa, et al.
    • Journal Title

      Neuroscience 184.4

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Biochemical and physical treatment in rat neuropathic pain and nerve growth factor.2004

    • Author(s)
      M.Nishi, T.Ishikawa, et al.
    • Journal Title

      PAIN RESEARCH. 19.4

      Pages: 141-149

    • NAID

      10013596382

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] INVOLVEMENT OF NERVE GROWTH FACTOR IN RAT NEUROPATHIC PAIN.2004

    • Author(s)
      O.Nakanishi, T.Ishikawa, et al.
    • Journal Title

      Neuroscience 522.5

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] INFLAMMATORY MEDIATOR, 5HT DOES NOT INFLUENCE NGF-RELATED HYPERALGESIA IN RATS2004

    • Author(s)
      T.Ishikawa, Y.Matsumoto, et al.
    • Journal Title

      Neuroscience 289.8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hydrophobic dipeptide, Leu-Ile, protects against neuronal death by inducing BDNF and GDNF synthesis.2004

    • Author(s)
      Nitta A, Furukawa S, et al.
    • Journal Title

      J Neurosci Res 78

      Pages: 250-258

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Axonal regrowth downregulates the synthesis of glial cell line- derived neurotrophic factor in the lesioned rat sciatic nerve.2004

    • Author(s)
      Yamada Y, Furukawa S, et al.
    • Journal Title

      J Neuro Lett. 364

      Pages: 11-15

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Mild hypothermia inhibits IL-10 production in peripheral blood Mononuclear cells.2004

    • Author(s)
      Matsui T, Ishikawa T, et al.
    • Journal Title

      Acta Anaesthesiol.Scand. 48

      Pages: 205-210

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Magnetic Field Stimulation Improves Rat Neuropathic Pain : Possible Involvement of Nerve Growth Factor.2004

    • Author(s)
      T Ishikawa, M Nishi, et al.
    • Journal Title

      The 2nd Asian Pain Symposium(proceeding) 54

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Inflammatory Mediator, Noradrenaline Possibly Influence NGF-related Hyperalgesia in Rats.2004

    • Author(s)
      K Yamaguchi, T Ishikawa, et al.
    • Journal Title

      The 2nd Asian Pain Symposium(proceeding) 56

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] COX-1 and COX-2 Dependent Release of PGE2 from LPS-activated Spinal Microglia.2004

    • Author(s)
      T Matsui, T Ishikawa, et al.
    • Journal Title

      The 2nd Asian Pain Symposium(proceeding) 64

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Neuroplasticity and stem cell treatment in spinal cord.2004

    • Author(s)
      Ishikawa T., Takano Y., et al.
    • Journal Title

      Jan J Clin Anesth. Vol.24 (1)

      Pages: 31-72

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Simultaneous transplantation of bone marrow stromal cells into spinal cord parenchyma and onto dura decreases spinal cord degeneration after injury2004

    • Author(s)
      H.Kataoka, T.Ishikawa, et al.
    • Journal Title

      Neuroscience

    • Related Report
      2004 Annual Research Report
  • [Journal Article] cAMP/protein Kinase A signalattentuates Ca^<2+>-induced fibroblast growth factor-1 synthesis in rat cortical neurons2004

    • Author(s)
      Kinukawa H, Furukawa S, et al.
    • Journal Title

      J Neurosci Res 77

      Pages: 487-497

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effects of stellate ganglion block on traumatic trigeminal neuropathy2003

    • Author(s)
      Sakamoto E, Ishikawa T., et al.
    • Journal Title

      Pain Research Vol.18 No.1

      Pages: 25-30

    • NAID

      10010514507

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increased glutamate release evokes neuroplasticty of spinal cord neurons which may develop neuropathic pain in rats2003

    • Author(s)
      Ishikawa T., Nishi M, et al.
    • Journal Title

      The 1^<st> Science and Research Symposium (proceeding)

      Pages: 38-38

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effects of stellate ganglion block on traumatic trigeminal neuropathy.2003

    • Author(s)
      Sakamoto E., Ishikawa T., et al.
    • Journal Title

      Pain Research Vol.18 No.1

      Pages: 25-30

    • NAID

      10010514507

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Increased glutamate release evokes neuroplasticty of spinal cord neurons which may develop neuropathic pain in rats2003

    • Author(s)
      Ishikawa T., Nishi M., et al.
    • Journal Title

      The 1^<st> Science and Research Symposium (proceeding) 38

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A Novel Ca Channel blocker, Cilnidipine, Inhibits Formalin-evoked Pain Responses in Relation to Spinal Glutamate Release in Rats.

    • Author(s)
      Y.Matsumoto, T.Ishikawa, et al.
    • Journal Title

      Neurosci Lets (in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] セロトニン研究会報告;神経因性疼痛の発生・維持における脊髄神経可塑性の関与2003

    • Author(s)
      石川 敏三 他
    • Total Pages
      70
    • Publisher
      セロトニン研究会
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Ishikawa T., Takano Y., et al.: "International Symposium on Spinal Cord Sciences : Neuroplasticity and stem cell treatment in spinal cord"日本臨床麻酔学会誌. Vol.24 No.1. 31-72 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ishikawa T., et al.: "Role of neuroplasticity of spinal sensory systems in neuropathic pain : assessed by modulatory effects of inhibition of afferent nerve activation"Soc Neurosci. (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sakamoto E., Ishikawa T., et al.: "Effects of stellate ganglion block on traumatic trigeminal neuropathy"Pain Research. Vol.18 No.1. 25-30 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ishikawa T., Nishi M., et al.: "Increased glutamate release evokes neuroplasticty of spinal cord neurons which may develop neuropathic pain in rats"The 1^<st> International Science and Research Symposium. 38-38 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Matsui T., Ishikawa T., et al.: "Mild hypothermia inhibits IL-10 production in peripheral blood mononuclear cells"Acta Anaesthesiol Scand. 48. 205-210 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ishikawa T., Nishi M., et al.: "Biochemical and physical treatment in rat neuropathic pain and nerve growth factor"Pain Research. Vol.19 No.2(印刷中). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 石川 敏三, 他: "セロトニン研究会報告:神経因性疼痛の発生・維持における脊髄神経可塑性の関与"セロトニン研究会. 70 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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