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Elucidation of Mechanism of Pain Transmission by Gene Targeting

Research Project

Project/Area Number 09480168
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Functional biochemistry
Research InstitutionKansai Medical University

Principal Investigator

ITO Seiji  Kansai Medical University, Faculty of Medicine, Professor, 医学部, 教授 (80201325)

Co-Investigator(Kenkyū-buntansha) MINAMI Toshiaki  Osaka Medical College, Faculty of Medicine, Assistant Professor, 医学部, 助手 (00257841)
NISHIZAWA Mikio  Kansai Medical University, Faculty of Medicine, Lecturer, 医学部, 講師 (40192687)
Project Period (FY) 1997 – 1998
Project Status Completed (Fiscal Year 1998)
Budget Amount *help
¥6,600,000 (Direct Cost: ¥6,600,000)
Fiscal Year 1998: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 1997: ¥3,900,000 (Direct Cost: ¥3,900,000)
Keywordsknockout mice / allodynia / hyperalgesia / prostaglandin D_2 / prostaglandin E_2 / GABA / opioid / prostaglandin D synthase / プロスタグランジンD合成酵素 / グルタミン酸受容体 / プロスタグランジンF_2α
Research Abstract

Prolonged inflammation and nerve injury often lead to chronic pain such that noxious stimuli evoke hyperalgesia and innocuous tactile stimuli evoke pain (allodynia). With the advent of molecular biology, substance P and glutamate have been shown to be involved in acute pain and hyperalgesia, but a factor(s) involving allodynia had remained to be known. We found that intrathecal administration of prostaglandin E_2 induced allodynia in conscious mice and established an in vivo allodynia model. These several years, we have pharmacologically elucidated the mechanism of allodynia by use of receptor agonists and antagonists. Here, we applied this model to mice lacking lipocalin-type PGD synthase (L-PGDS) and obtained following results.
While hyperalgesia induced by PGD_2 and PGE_2 was observed in L-PGDS-/- mice as well as wild-type mice, PGE_2-induced allodynia was not observed in L-PGDS-/-. Simultaneous administration of a femtogram amount of PGD_2 with PGE_2 induced allodynia in L-PGDS-/- m … More ice to the same extent as in wild-type mice. These results demonstrate that POD_2 is essential for induction of PGE_2-induced allodynia. Because PGD_2 blocked PGE_2-induced allodynia at a pg level, these experiments with PGDS-/- knockout mice first demonstrate that PGD_2 may regulate the induction of PGE_2-induced allodynia biphasically. Furthermore, the inhibitory amino acid GABA was suggested to mediate the action of PGD_2. At present experiments with knockout mice lacking other PG synthases and PG receptors are under investigation. Until recently, it was generally accepted that PGs act on pain transmission in the periphery and that opioids act, in the central nervous system. With the aid of developmental technology and genetargeting techniques, we have shown that both POs and opioids play important roles in induction of allodynia at the molecular level. We have recently succeeded in isolation of a novel peptide nocistatin from the brain and the cloning and characterization of its receptor are in progress. Less

Report

(3 results)
  • 1998 Annual Research Report   Final Research Report Summary
  • 1997 Annual Research Report
  • Research Products

    (24 results)

All Other

All Publications (24 results)

  • [Publications] Okuda-Ashitaka, E.: "Nocistatin, a peptide that blocks nociceptin action in pain transmission." Nature. 392. 285-289 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakai, M.: "Prostaglandin E_2 induced nitric oxide release from rat spinal cord." Br. J. Pharmacol.123. 890-894 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Minami, T.: "Anti-nociceptive responses produced by human counterpart of nocistatin." Br. J. Pharmacol.124. 1016-1018 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nicol, B.: "Nocistatin reverses nociceptin inhibition of glutamate release from rat brain slices." Eur. J. Pharmacol.356. R1-R3 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Eguchi, N.: "Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-dificient mice." Proc. Natl. Acad. Sci. USA. 96. 726-730 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Minami, M.: "Involvement of primary afferent C-fibers in touch-evoked pain (allodynia) induced by prostaglandin E_2" Eur. J. Neurosci.in press. (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuda-Ashitaka, E: "Nocistatin, a peptide that blocks nociceptin action in pain transmission." Nature. 392. 286-289 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Sakai, M: "Prostaglandin E_2 induced nitric oxide release from rat spinal cord." Br.J.Pharmacol. 123. 890-894 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Minami, T: "Anti-nociceptive responses produced by human counterpart of nocistatin." Br.J.Pharmacol. 124. 1016-1018 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Nicol, B: "Nocistatin reverses nociceptin inhibition of glutamate release from rat brain slices." Eur.J.Pharmacol. 356. R1-R3 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Eguchi, N: "Lack of tactile pain (allodynia) in lipocalin-type prostaglandin D synthase-dificient mice." Proc.Natl.Acad.Sci.USA. 96. 726-730 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Mminami, M.: "Involvement of primary afferent C-fibers in touchevoked pain (allodynia) induced by prostaglandin E_2." Eur.J.Neurosci. (in press). (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1998 Final Research Report Summary
  • [Publications] Okuda-Ashitaka,E.: "Nocistatin,a peptide that blocks nociceptin action in pain transmission." Nature. 392. 286-289 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Sakai,M.: "Prostaglandin E_2 induced nitric oxide release from rat spinal cord." Br.J.Pharmacol.123. 890-894 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Minami,T.: "Anti-nociceptive responses produced by human counterpart of nocistatin." Br.J.Pharmacol.124. 1016-1018 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Nicol,B.: "Nocistatin reverses nociceptin inhibition of glutamate release from rat brain slices." Eur.J.Pharmacol.356. R1-R3 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Eguchi,N.: "Lack of tactile pain(allodynia)in lipocalin-type prostaglandin D synthase-dificient mice." Proc.Natl.Acad.Sci.USA. 96. 726-730 (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Minami,M.: "Involvement of primary afferent C-fibers in touch-evoked pain(allodynia)induced by prostaglandin E_2." Eur.J.Neurosci.(in press). (1999)

    • Related Report
      1998 Annual Research Report
  • [Publications] Minami,T.: "Absence of prostaglandin E_2-induced hyperalgesia in NMDA receptorε subunit knockout mice." Br.J.Pharmacol.120. 1522-1526 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Hara,N.: "Characterization of nociceptin hyperalgesla and allodynia in conscious mice." Br.J.Pharmacol.121. 401-408 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Ezashi,T.: "Genomic prganization and characterization of the gene encoding bovine prostaglandin F_2α receptor." Gene. 190. 271-278 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Minami,T.: "Inhibition of nociceptin-induced allodynia in conscious mice by prostaglandin D_2." Br.J.Pharmacol.122. 605-610 (1997)

    • Related Report
      1997 Annual Research Report
  • [Publications] Okuda-Ashitaka,E.: "Nocistatin:a peptide blocking nociceptin action in pain transmission." Nature. (in press).

    • Related Report
      1997 Annual Research Report
  • [Publications] Sakai,M.: "Prostaglandin E_2 induced nitric oxide release from rat spinal cord." Br.J.Pharmacol.(in press).

    • Related Report
      1997 Annual Research Report

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Published: 1997-04-01   Modified: 2016-04-21  

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