| Project/Area Number |
14370027
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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 |
General pharmacology
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| Research Institution | Tohoku University |
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Principal Investigator |
YANAI Kazuhiko Tohoku University, Graduate School of Medicine, Professor, 大学院・医学系研究科, 教授 (50192787)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Takehiko Tohoku University, Graduate School of Medicine, Professor Emeritus, 名誉教授 (70028356)
TASHIRO Manabu Tohoku University, Cyclotron and Radioisotope Center, Lecturer, サイクロトロンRIセンター, 講師 (00333477)
KURAMASU Atsuo Tohoku University, Graduate School of Medicine, Lecturer, 大学院・医学系研究科, 講師 (90302091)
OKAMURA Nobuyuki Tohoku University, Graduate School of Medicine, Research Associate, 大学院・医学系研究科, 助手 (40361076)
ISHIWATA Kiichi Tokyo Metropolitan Institute of Gerontology, Chief Investigator, 主任研究員 (50143037)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥13,900,000 (Direct Cost: ¥13,900,000)
Fiscal Year 2004: ¥2,700,000 (Direct Cost: ¥2,700,000)
Fiscal Year 2003: ¥4,000,000 (Direct Cost: ¥4,000,000)
Fiscal Year 2002: ¥7,200,000 (Direct Cost: ¥7,200,000)
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| Keywords | Orexins / Histamine / Adenosine / Pain perception / Antinocicention / gene knockout mice / Schizouhrenia / Positron Emission Tomography(PET) / 痛み / activity stress / 神経性食欲低下症 / うつ病 / ドキセピン / ハロペリドール / 覚醒 / 脳血流量 / ノックアウトマウス / モルヒネ |
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| Research Abstract |
Orexins are neuropeptides located exclusively in neurons of the lateral hypothalamic area, which send projections to most monoaminergic nuclei, such as noradrenergic locus coeruleus, dopaminergic ventral tegmental areas, and histaminergic tuberomammillary nuclei. The present work was carried out to examine the role of orexins in nociception in mice. C57BL/6 mice were administered with orexin A and B intracerebroventricularly(i.c.v.), intrathecally(i.t.) and subcutaneously(s.c.) to reveal the sites of action of these peptides and to examine the pain thresholds using four kinds of nociceptive tasks. Orexins showed antinociceptive effects in all four types of assays for thermal (hot-plate, tail-flick, paw-withdrawal), mechanical (tail-pressure), chemical (formalin, capsaicin and abdominal stretch) nociceptions and nociceptininduced behavioral responses, when administered i.c.v. or i.t., whereas the s.c. administration was ineffective. The antinociceptive effects of orexin A were more rema
… More
rkable than those of orexin B. The i.c.v. administration of orexin A was as effective as, or more potent than the i.t. administration. The effects of orexinAwere completely blocked by adenosine type 1 receptor antagonists, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) and theophylline, but not by naloxone, suggesting a possible involvement of the adenosine-containing neurons and/or the adenosine pathway in these orexin actions. The i.c.v. administration of nociceptin had no significant effects on orexin expression in the brain and spinal cord. The present findings suggest that orexins have an antinociceptive role in at least four different types of pains, probably acting on both the brain and spinal cord.
Increasing evidence has shown that the histaminergic neuron system is implicated in the pathophysiology of schizophrenia. The aim of this study was to compare the distribution of histamine H_1 receptors between schizophrenics and normal human subjects in vivo using positron emission tomography (PET). H_1 receptor binding was measured in 10 normal subjects and 10 medicated schizophrenic patients by PET and [^<11>C] doxepin, a radioligand for the H_1 receptor. The binding potential (BP=Bmax/K_D) of [^<11>C] doxepin for available brain H_1 receptors was calculated by a graphical analysis on voxel-by-voxel basis and compared between schizophrenics and normal subjects using the regions of interest (ROIs) and the statistical parametrical mapping (SPM99). BP values for H_1 receptors in the frontal and prefrontal cortices and the cingulate gyrus were significantly lower among the schizophrenic patients than among the control subjects. On the contrary, there were no areas of the brain where H_1 receptors were significantly higher among the schizophrenic patients than the control subjects. The results of our study suggest that the central histaminergic neuron system could be involved in the pathophysiology of schizophrenia, although further studies are needed to confirm this hypothesis. Less
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