| Project/Area Number |
06454444
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
Anesthesiology/Resuscitation studies
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| Research Institution | Yamaguchi University |
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Principal Investigator |
ISHIKAWA Toshizo Yamaguchi Univ.Sch.of Med., Research Associate, 医学部, 助手 (90034991)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAKIMURA Kazuhiko Yamaguchi Univ.Sch.of Med., Assistant Professor, 医学部・附属病院, 講師 (50180261)
MAEKAWA Tsuyoshi Yamaguchi Univ.School of Medicine, Professor, 医学部, 教授 (60034972)
SAKABE Takefumi Yamaguchi Univ.School of Medicine, Professor, 医学部, 教授 (40035225)
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| Project Period (FY) |
1994 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 1995: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 1994: ¥3,100,000 (Direct Cost: ¥3,100,000)
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| Keywords | Pain / Spinal sensitization / Hyperalgesia / Spinal glutamate / PKC / NGF / 疼痛 / 脊髄過敏 / 痛覚過敏 / 触覚過敏 / 脊髄マイクロダイアリス / グルタメート放出 / プロテインキナーゼC / 神経成長因子 / 細胞内情報伝達系 / Cキナーゼ / 細胞骨格蛋白 / 神経栄養因子 / シナプス可塑性 / 脱抑制機構 |
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| Research Abstract |
The somatosensory system of spinal cord are directly involved into the modulation of peripheral nociceptive input with acute and/or chronic peripheral C-fibers activation following tissue injury. However, under certain condition, there is a pathological state which is functionally characterized by an increased response to noxious stimuli (hyperalgesia), and the reduction of pain threshold (allodynia). The aim of the present study was to examine the molecullar mechanism of the observed pathological pain state may reflect an abnormal intracellular signaling resulting in increased intracellular Ca ion caused by excessive release of glutamate and substance P and increased syntheses of a variety of growth factors (NGF) using well-established rat model.
The followings are possible mechanisms based on the present study.
1.Pain and neuronal plasticity following peripheral tissue inflammation
Increased peripheral C-fiber activity resulting from formalin or mustard oil hind paw injection evokes 1)
… More
excessive release of spinal glutamate (by microdialysis), 2) NMDA antagonist blocked hyperalgesia-> increased neuronal activity of dorsal horn resulting from activation of NMDA receptor and corresponding massive increase in intracellular Ca^<++>,3) Staurosporine (PKC inhivitor) supressed glutamate release and hyperalgesia -> activation of PLA2, PLC which evokes synthesis of arachidonic acid (PGs) and protein kinase C (PKC), these substances and enzyme iniciate positive feed back in spinal cord (sustained facilitation), 4) "up-regulation" of synaptic transmission within the spinal cord functionally expressed as 5) increased responsivity of spinal cord neurons to peripheral stimulus i.c. "central sensitization" : allodynia and/or hyperalgesia.
2.Involvement of nerve growth factor (NGF) in facilitated pain state.
The biological role of NGF in the developing and restoring processes after peripheral nerve injury has been most intensively studied. There is evidence suggesting its role as a target-derived neurotrophic factor, regulating the density of innervation in a variety of peripheral tissues. The role of NGF in the adult animal is less well characterized, but there is increasing evidence including present results to suggest that NGF is a peripheral mediator in facilitated inflammatory pain states. 1) the high affinity NGF receptor is expressed with sP in C-fiber (trkA),
2) 4-methyl cathechol (4MC), which increases NGF,caused enhancement of hyperalgesia in a dosc deppendent manner produced by injecting mustard oil. -> NGF treatment can facilitate glutamate and sP mediated synaptic transmission, and can lead to central sensitization. 3) NGF immunoreactivity of spinal cord was increased to compensate dendritic damage of neuron (decreased MAP-2 immunoreactivity) after formalin injection -> this may be caused by interacting with interleukin-1 (IL-1) * activated macrophage where the IL-1 is the key mediator on NGF-mRNA levels.
Taken together, these evidences strongly suggest that NGF is necessary for the maintenance of the up-regulation can lead to a peripheral and central sensitization. In the future study, we need to elucidate further such as the theories proposed to explain how the peripheral injury or noxicious stimulation lead to the alteration in neuronal plasticity and how to play a role of NGF in facilitating state and neuronal degeneration in chronic state. Less
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