2000 Fiscal Year Final Research Report Summary
Elucidation of mechanism for induction of pain with knockout mice
| Project/Area Number |
11470044
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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 |
Pathological medical chemistry
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| Research Institution | Kansai Medical University |
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Principal Investigator |
ITO Seiji Kansai Medical University, Medicine, Professor, 医学部, 教授 (80201325)
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| Co-Investigator(Kenkyū-buntansha) |
URADE Yoshihiro Osaka Bioscience Institute, 2<@D1nd@>D1 Dept. (Molecular Behavioral Biology), Head, 第2部門, 部長 (10201360)
MATSUMURA Shinji Kansai Medical University, Medicine Assistant Professor, 医学部, 助手 (70276393)
OKUDA-ASHITAKA Emiko Kansai Medical University, Medicine Lecturer, 医学部, 講師 (50291802)
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| Project Period (FY) |
1999 – 2000
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| Keywords | pain / allodynia / knockout mice / sciatic nerve injury model / prostaglandin / cyclooxygenase / NMDA receptors / nitric oxide synthase |
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| Research Abstract |
The sensation of pain provides useful warning about occurrence of injury. However, under pathological conditions such as prolonged inflammation, post-operation, and nerve injury, nociceptors in the periphery become activeted and produce spontaneous pain, hyperalgesia and tactile pain (allodynia). We previously demonstrated that 1) intrathecal administration of prostaglandin (PG) E2 and PGF2α induced allodynia, 2) capsaicin-sensitive and-insensitive pathways were involved in induction of allodynia, 3) PGs may produce allodynia by initiating a biochamical cascade of glutamate release from synaptic terminal→activation of NMDA receptor→NO production. 4) PGD2 blocked the PGE2-induced allodynia. In order to clarify the involvement of a given component in induction of allodynia by use of knockout mice, we established partial sciatic nerve ligation method in the knockout mouse and obtained following results.
Cyclooxygenases (COXs) are rate-limiting enzymes for PG production. While COX-1 is a constitutive form, COX-2 is an inducible form and considered to be accounted for PG production in inflammation. 1) Although allodynia was induced 1 week after treatment, allodynia was observed in COX-2^<-/-> mice, suggesting that COX-2 was not involved in the induction of allodynia. 2) The COX-1 selective inhibitor, but not the COX-2 selective inhibitor, alleviated pain responses induced by sciatic nerve injury. 3) While allodynia was observed in iNOS^<-/-> mice, pain responses disappeared in NMDA^<-/-> mice. These results demonstrate that excitatory transmission by glutamate activated by PGE2 plays pivotal roles in induction and maintenance of pain following sciatic nerve injury. In order to elucidate the induction and maintenance of allodynia, we will extend this study of sciatic nerve injury model and compare it with that of i.t. PG allodynia model.
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