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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

食欲素是一种神经肽，仅存在于下丘脑外侧区的神经元中，它向大多数单胺能核发送投射，例如去甲肾上腺素能蓝斑、多巴胺能腹侧被盖区和组胺能结节乳头核。目前的工作是为了检查食欲素在小鼠伤害感受中的作用。 C57BL/6 小鼠脑室内 (i.c.v.)、鞘内 (i.t.) 和皮下 (s.c.) 施用食欲素 A 和 B，以揭示这些肽的作用位点，并使用四种伤害性任务检查疼痛阈值。当静脉注射时，食欲素在所有四种类型的热（热板、甩尾、缩爪）、机械（尾部压力）、化学（福尔马林、辣椒素和腹部拉伸）伤害感受和伤害感受肽诱导的行为反应测定中均显示出抗伤害作用。或 i.t.，而 s.c.行政管理无效。食欲素 A 的抗伤害作用比食欲素 B 更显着。施用食欲素 A 与 i.t. 一样有效，甚至更有效。行政。食欲素 A 的作用被 1 型腺苷受体拮抗剂、1,3-二丙基-8-环戊基黄嘌呤 (DPCPX) 和茶碱完全阻断，但不被纳洛酮阻断，表明含腺苷神经元和/或腺苷途径可能参与这些食欲素作用。 i.c.v.给予伤害感受肽对大脑和脊髓中食欲素的表达没有显着影响。目前的研究结果表明，食欲素在至少四种不同类型的疼痛中具有抗伤害作用，可能同时作用于大脑和脊髓。越来越多的证据表明，组胺能神经元系统与精神分裂症的病理生理学有关。本研究的目的是使用正电子发射断层扫描（PET）比较精神分裂症患者和正常人体内组胺 H_1 受体的分布。通过PET和[11C]多塞平(H_1受体的放射性配体)在10名正常受试者和10名药物治疗的精神分裂症患者中测量H_1受体结合。 [^ 11 C]多塞平对可用脑H_1受体的结合潜力(BP＝Bmax/K_D)通过逐个体素的图形分析来计算，并使用感兴趣区域(ROI)和统计参数映射(SPM99)在精神分裂症患者和正常受试者之间进行比较。精神分裂症患者额叶、前额皮质和扣带回H_1受体的血压值显着低于对照组。相反，精神分裂症患者大脑中没有任何区域的H_1受体明显高于对照组。我们的研究结果表明，中枢组胺能神经元系统可能参与精神分裂症的病理生理学，尽管需要进一步的研究来证实这一假设。较少的