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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

食欲素是专门位于下丘脑外侧区的神经元中的神经肽，其将投射发送到大多数单胺能核，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。本研究旨在探讨食欲素在小鼠伤害感受中的作用。向C57 BL/6小鼠脑室内（i. c. v.）施用食欲素A和B，鞘内（i.t.）和皮下（s.c.）揭示这些肽的作用部位，并使用四种伤害性任务检查痛阈值。食欲素在所有四种类型的热（热板、甩尾、缩爪）、机械（尾压）、化学（福尔马林、辣椒素和腹部拉伸）伤害感受和伤害感受素诱导的行为反应的测定中显示出抗伤害感受作用，当i. c. v.或i.t.给药时，而s.c.管理是无效的。增食欲素A的抗伤害作用更明显， ...更多信息比增食欲素B更有效。食欲素A的i. c. v.给药与i.t.局orexinA的作用被腺苷1型受体拮抗剂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，这表明含腺苷神经元和/或腺苷通路可能参与这些orexin的作用。i. c. v.给药孤啡肽对大脑和脊髓中的食欲素表达没有显著影响。目前的研究结果表明，食欲素有至少四种不同类型的疼痛，可能同时作用于大脑和脊髓的镇痛作用。越来越多的证据表明，组胺能神经元系统是牵连在精神分裂症的病理生理。本研究的目的是利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H1受体的分布。用正电子发射断层显像（PET）和H_1受体的放射性配体多塞平（doxepin）测定了10例正常人和10例药物治疗的精神分裂症患者的H_1受体结合<11>。用<11>感兴趣区（ROI）和统计参数图（SPM 99）计算了精神分裂症患者和正常人脑H_1受体的结合电位（BP=Bmax/K_D）。额叶、前额叶皮质和扣带回H_1受体的BP值在精神分裂症组明显低于对照组。而精神分裂症患者脑内H_1受体无明显增高。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，但需要进一步的研究来证实这一假设。少