| Project/Area Number |
13470328
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Osaka Medical College |
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Principal Investigator |
MINAMI Toshiaki Osaka Medical College Faculty of Medicine Professor, 医学部, 教授 (00257841)
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| Co-Investigator(Kenkyū-buntansha) |
MATSUMURA Shinji Osaka Medical College Faculty of Medicine Research Assistant, 医学部, 助手 (70276393)
HARA Naoki Osaka Medical College Faculty of Medicine Research Assistant, 医学部, 助手 (60298768)
SAKAI Masato Osaka Medical College Faculty of Medicine Assistant Professor, 医学部, 講師 (30319545)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,500,000 (Direct Cost: ¥12,500,000)
Fiscal Year 2002: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2001: ¥7,900,000 (Direct Cost: ¥7,900,000)
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| Keywords | Allodynia / Knockout mice / Prostaglandin / Prostacyclin / Nociceptin / Nocistatin / Glutamate / Capsaicin / 痛覚過敏反応 / 炎症性疼痛 / 神経因性疼痛 / プロスタグランジン |
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| Research Abstract |
Characterization of the glutamatergic system for induction and maintenance of allodynia
We previously demonstrated that intrathecal (i.t.) administration of PGE_2 and PGF_<2α> induced touch-evoked pain (allodynia) through the glutamatergic system by different mechanisms. In the present study, we characterized NMDA receptor subtypes and glutamate transporters involved in induction and maintenance of PGE_2- and PGF_<2α>-evoked allodynia. PGE_2-induced allodynia was observed in NMDA receptor ε4 (NR2D) subunit knockout [GluRε4(-/-)] mice, but not in ε1 (NR2A) subunit knockout [GluRε1(-/-)] mice. Conversely, PGF_<2α>-induced allodynia were observed in GluRε1(-/-) mice, but not in GluRε4(-/-) mice. The induction of allodynia by PGE_2 was abolished by the NMDA receptor ε2 (NR2B) antagonist CP-101,606 and neonatal capsaicin treatment. PGF_<2α>-induced allodynia were not affected by CP-101,606 and by neonatal capsaicin treatment. On the other hand, the glutamate transporter blocker DL-TBOA block
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ed both the allodynia induced by PGE_2 and PGF_<2α>. These results demonstrate that there are two pathways for induction of allodynia mediated by the glutamatergic system and suggest that the glutamate transporter is essential for the induction and maintenance of allodynia.
Characterization of nociceptin/orphanin FQ-induced pain responses
At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pro-nociceptive and allodynic effects at low doses (pg range), while causing anti-nociceptive effects at high doses (μg range). The discrepancy of pain modulation by Noc/OFQ at doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. We examined the involvement of the Noc/OFQ receptor in pain responses with the novel non-peptide antagonist JTC-801. Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ were dose-dependently blocked by simultaneous administration of JTC-801. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, while it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1μg. While the pro-nociceptive effect by 10 pg Noc/OFQ was dose-dependently blocked by JTC-801, the anti-nociceptive effects by 1 μg Noc/OFQ were not antagonized by JTC-801. These results with JTC-801 demonstrate that pro-nociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that the anti-nociceptive effect by a high dose of Noc/OFQ in the formalin test may be mediated through a receptor besides the cloned Noc/OFQ receptor. Less
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