| Project/Area Number |
17591569
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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 |
Orthopaedic surgery
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| Research Institution | Mie University |
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Principal Investigator |
WAKABAYASHI Hiroki Mie University, Postgraduate School of Medicine, Department of Orthopaedic Surgery, Assistant Professor, 大学院医学系研究科, 助手 (50362687)
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| Co-Investigator(Kenkyū-buntansha) |
YONEDA Toshiyuki Osaka University, Postgraduate School of Dentistry, Department of Biochemistry, Professor, 歯学研究科, 教授 (80142313)
UCHIDA Atsumasa Mie University, Postgraduate School of Medicine, Department of Orthopaedic Surgery, Professor, 大学院医学系研究科, 教授 (40176681)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥1,500,000 (Direct Cost: ¥1,500,000)
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| Keywords | Bone metasitasis / Acidosis / TRPV1 |
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| Research Abstract |
Bone pain is one of the major complications that affects QOL of cancer patients with bone metastases. Although the precise mechanism of bone pain is still unclear, the widely-known clinical observations that specific inhibitors of bone resorption bisphosphonates (BPs) reduce bone pain suggest a potential role of osteoclasts that play a central role in bone metastases. Osteoclasts dissolve bone minerals by releasing protons through the vacuolar type proton pump, thereby inducing acidosis, which is a well-known cause of pain. Recent studies have shown that acidosis directly activates the transient receptor potential channel-vanilloid 1 (TRPV1) that converts pain signals to the central nervous system. We studied the role of TRPV1 in the induction of bone pain associated with cancer colonization in bone.
Histological examination showed that TRPV1 was expressed together with calcitonin gene-related protein (CGRP)-positive sensory neurons in periosteum, cortical bone and bone marrow and dorsa
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l root ganglion (DRG). To study the role of TRPV1, we established an animal model of cancer-induced bone pain by inoculating cancer cells into tibiae in syngeneic wild-type (WT) and TRPV1-deficient (TRPV-/-) mice. In WT mice, tumor-inoculated tibiae showed hyperalgesia, decreased grip force and increased flinching compared with control tibiae, suggesting increased bone pain. TRPV1-immunoreactive fibers were increased in tumor-inoculated bone compared with control bones. In contrast to WT mice, there were no differences in the hyperalgesia and grip force between bones with and without cancer cells in TRPV1-/-mice. Flinching of tumor-inoculated hind-limbs in TRPV1-/-mice was significantly less than WT mice. Number of phosphorylated ERK (p-ERK) immunorceactive neurons in DRG was greater in WT mice than TRPV1-/-mice.
We established an in vitro having pain model by DRG organ culture in 2006. TRPV1 protein increased in immunoprecipitation when we added acid stimulation to organ cultured DRG. In addition p-ERK protein increased in acid stimulation in organ cultured DRG of WT mice, and TRPV1 selective inhibitor inhibited the increased p-ERK protein. The influence was absent in manifestation of acid stimulation and a TRPV1 selective inhibitor in DRG of TRPV1-/-mice.
In conclusion, our results suggest that TRPV1 activation in the sensory neurons innervating bone by the acidic microenvironment in cancer-induced bone pain. Less
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