A study of the histamine neuron system : Its correlation to newly-discovered hypothalamic peptides.

组胺神经元系统的研究：其与新发现的下丘脑肽的相关性。

基本信息

批准号：
14370027
负责人：
YANAI Kazuhiko
金额：
$ 8.9万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

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

Orexins是独家位于下丘脑区域神经元中的神经肽，它们向大多数单胺能核能发送投影，例如Noradrenagic locus coeruleus，多巴胺能腹侧侧侧段落以及组氨基酰胺能Tuberomillary核核。目前的工作是为了检查小鼠在伤害受伤吸引力中的作用。用Orexin A和B室内（i.c.v。），胸前（i.t。）和皮质（s.c。）施用C57BL/6小鼠，以揭示这些Petides的作用部位，并使用四种伤害性的伤害性任务来揭示这些宠物的作用部位并检查疼痛阈值。在所有四种类型的测定中，甲状腺素在所有四种类型的测定中都表现出对热的测定（热板，尾灯，爪子抽水），机械（尾压），化学（福尔马林，辣椒蛋白和腹部伸展）的伤害感受器，并在给予伤害摄影剂时，当给药时i.c.v. i.c.v.或I.T.，而S.C.管理无效。 Orexin A的抗心敏作用比Orexin B.与I.T.的施用Orexin A具有与I.T.一样有效或更有潜力行政。腺苷1型受体拮抗剂，1,3-二甲基-8-圆锥黄甘氨酸（DPCPX）和芬林完全阻断了Orexinawere的影响，但没有由Naloxone，这表明可能会涉及腺苷神经元和/或或或或或或或或或或腺苷途径的腺苷行动。 I.C.V.耐生虫的给药对脑和脊髓中的Orexin表达没有显着影响。目前的发现表明，在至少四种不同类型的疼痛中，奥雷蛋白在大脑和脊髓上都具有抗伤害感受的作用。提出的证据表明，这项研究的目的是实施了组胺能神经元系统，以比较使用精神分裂药物和正常人在Vivo中的组胺H_1受体的分布，并使用Vivo Insision Insision Insision（Tomecripe insife）（Tomecrape）（Tomecrape）（Tomecrape）。在10个正常受试者中测量了H_1受体结合，并通过PET和[^<11> c] doxepin（H_1受体的放射性物体）测量了10名药物精神分裂症患者。用于可用脑H_1受体的[^<11> C] doxepin的结合电位（BP = BMAX/K_D）通过对素素基基础的图形分析计算，并使用兴趣区域（ROIS）和统计参数映射（SPM99）进行了图形分析。精神分裂症患者中额叶和额叶皮层和扣带回的H_1受体的BP值明显低于对照组受试者。相反，精神分裂症患者中H_1受体显着高于对照组受试者，没有大脑的区域。我们的研究结果表明，尽管需要进一步的研究来证实这一假设，但中央组胺能神经元系统可能与精神分裂症的病理生理有关。较少的