| Project/Area Number |
18592036
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Functional basic dentistry
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| Research Institution | Hiroshima University |
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Principal Investigator |
MORITA Katsuya Hiroshima University, Graduate School of Biomedical Sciences, Associate Professor (10116684)
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| Co-Investigator(Kenkyū-buntansha) |
DOHI Toshihiro Hiroshima University, Graduate School of Biomedical Sciences, Professor (00034182)
KITAYAMA Tomoya Hiroshima Univ., Graduate School of Biomedical Sciences, Assistant Professor (60363082)
MORIOKA Norimitsu Hiroshima Univ., Graduate School of Biomedical Sciences, Assistant Professor (20346505)
KITAYAMA Shigeo Okayama University, Graduate School of Biomedical Sciences, Professor (80177873)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,930,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,500,000 (Direct Cost: ¥2,500,000)
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| Keywords | neuropathic pain / allodynia / cyclic ADP-ribase (cADPR) / descending inhibitory neuron / glycine receptor α3 (GlyRα3) / spinal pain sensation / neucleoside transpoter (NT) / NT inhibitor / 環状ADPリボース / 痛覚伝達制御 / 抗アロディニア作用 / 鎮痛薬 / 抗炎症薬 / 環状ADP-リポース |
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| Research Abstract |
Cyclic ADP-ribose (cADPR), identified as a novel Ca^<2+>-mobilizing agent, has been involved in a many cellular functions. However, its role in mediation of nociception in central nervous system is unknown. In the present study, whether cADPR plays some role in pain transduction in the spinal cord was studied in mice. We demonstrated that cADPR was synthesized extracellularly by CD38, transported into the cells through nucleoside transporters (NTs), and then Ca^<2+> was mobilized by FK506-binding protein-dependent process. This process may be involved in migration in human neutrophils and in catecholamine release in adrenal chromaffin cells. Intrathecal injection (i. t. injection) of cADPR induced tactile pain, tactile allodynia at 0.01 to 5 nmole with a peak response at 1 nmole. Tactile allodynia induced by cADPR was blocked by a cADPR antagonist,8Br-cADPR. NT inhibitors (inosine, uridine or NBT-1, S-(p-notrobenzyl)-6-thioinosine), ryanodine receptor antagonist (ryanodine) or selective blocker of SERCA pump (thapsigargin) protected mice against the induction of allodynia induced by cADPR. CD38, NT and ryanodine receptor in the spinal cord may be involved in the mechanism of cADPR-induced tactile allodynia. This may also provide important information for understanding the underlying molecular mechanisms of the development of neuropathic pain.
Neuropathic pain is refractory against conventional analgesics, and thus novel medicaments are desired for treatment. In this study, we demonstrated that intravenous or i. t. administration of 8Br-cADPR, nucleoside transporter inhibitors, or knockdown of spinal CD38 by small interfering RNA of CD38 mRNA produced a profound antiallodynia effect in a partial sciatic nerve ligation model and other neuropathic and inflammatory pain models in mice. These results established CD38 and NT as the target molecules for the development of medicaments for neuropathic pain.
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