| Project/Area Number |
16209047
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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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 University |
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Principal Investigator |
MASHIMO TAKASHI Osaka University, Graduate School of Medicine, Professor (60157188)
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| Co-Investigator(Kenkyū-buntansha) |
SHIBUTA Satoshi Osaka University, Graduate School of Medicine, Assistant Professor (20324767)
SAKOU YASUSHI Osaka University, Graduate School of Frontier Biosciences, Associate Professor (20215700)
YANAGIDA TOSHIO Osaka University, Graduate School of Frontier Biosciences, Professor (30089883)
TANAKA YOSHIHARU Osaka Prefecture University, College of Integrated Arts and Sciences, Assistant (60236651)
内田 一郎 大阪大学, 医学系研究科, 助教授 (00232843)
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| Project Period (FY) |
2004 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥35,100,000 (Direct Cost: ¥27,000,000、Indirect Cost: ¥8,100,000)
Fiscal Year 2007: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2006: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
Fiscal Year 2005: ¥11,050,000 (Direct Cost: ¥8,500,000、Indirect Cost: ¥2,550,000)
Fiscal Year 2004: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
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| Keywords | Anesthetic, general and local / Molecular mechanism / Receptor / Structure / Dynamics / GABAA receptor / Tonic inhibition / 5-HT3 receptor / 電位固定法 / アミノ酸点変異 / 局所麻酔薬 / プロカイン / リドカイン / テトラカイン / ブピバカイン / 脊髄膠様質ニューロン / パッチクランプ法 / 抑制性後シナプス微小電流,mIPSC / プロポフォール / ミダゾラム / 全身麻酔 / 侵害受容 / キセノン / 亜酸化窒素 / 脊髄後根 / NMDA受容体 / NGF / 受容体 / 蛍光色素 / クラスター / 麻酔薬感受性 / エーテル / ジアゼパム |
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| Research Abstract |
Molecular identifications of general anesthetic targets in the receptor level has been progressed and the functional roles of their molecular targets are revealed by their integration of the in vivo system using the genetic engineering techniques.
1) Xenon suppresses nociceptive reflex in rat spinal cord in vitro ; comparison with nitrous oxide : The effect of xenon on slow ventral root potential and monosynaptic reflex in neonatal rat spinal cord in vitro in comparison with nitrous oxide. Xenon and nitrous oxide significantly reduced the amplitudes of both slow ventral root potential and monosynaptic reflex The results indicate that xenon and nitrous oxide suppress the synaptic transmission at the spinal cord, especially those of the slow ventral root potential, which refrect nociceptive transmission.
2) Formation of signal transduction complexes during immobile phase of NGF-receptor movements : The single-molecule imaging was used to characterize the behavior of Cy3-stagged NGF after b
… More
inding to receptor complexes on the surface of PC12 cell NGF-receptor complexes have two distinct diffusive states, characterized as mobile and immobile phase. The transition between the two diffusive states occurred reversibly with duration times determined by a single rate limiting process. Immobilization depended on the phosphorylation of the TrkA NGF-receptor. NGF signaling is performed through a repetitive random process to induce transition formation of signaling complexes.
3) General anesthetics potentiate GABAergic tonic inhibition of substantia gelatinosa neurons in mouse spinal cord.: Whole-cell recording was used to identify GABAergic tonic current in subpopulations of substantia gelatinosa neurons in mouse spinal cord slims. Application of the GABAA receptor antagonist bicuculline revealed tonic currents in some neurons for the first time. General anesthetics, midazolam and propofol potentiated these tonic currents. The presence of mRNAs for α4, α5, δ and εsubunits in the substantia geratinosa suggest that GABAAreceptors α5βxγ2 subunits are responsible for tonic currents.
4) Local anesthetics have different mechanisms and sites of action at recombinant 5-HT3 receptors : The cRNAs from human wild-type and 4 mutant 5-HT3A subunit clones were synthesized in vitro and expressed in Xenopus oocytes. Four mutant receptor were obtained by site-directed mutagenesis in the N-terminal extracellular region. The 2-electrode voltage clamp technique was used to measure peak currents induced by 5-HT in these receptors in the presence and absence of local anesthetics. All local anesthetics inhibited 5-HT-induced currents in the wild-type receptor. Inhibition by procaine and tetracaine were competitive whereas those of bupivacaine and lidocaine were both noncompetitive and competitive. All mutant receptors exhibited 10-fold increase in the half-maximum inhibitory concentration for procaine. The half-maximum inhibitory concentrations of tetracaine, bupivacaine, and lidocaine in mutant receptors were increased 2- to 3-fold. These results suggest that the ester type local anesthetics, procaine and tetracaine may act at a different site on the 5-HT3Areceptor and with a different mechanism than the amide-type local anesthetics. Less
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