| Project/Area Number |
16614003
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
睡眠学
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
HONDA Kazuki Tokyo Medical and Dental University, Institute of Biomaterials and Bioengineering, Associate Professor, 生体材料工学研究所, 助教授 (70173656)
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| Co-Investigator(Kenkyū-buntansha) |
IWASAKI Yasuhiko Tokyo Medical and Dental University, Associate Professor, 生体材料工学研究所, 助教授 (90280990)
KATAYAMA Yoshifumi Tokyo Medical and Dental University, Professor, 難治疾患研究所, 教授 (20014144)
HIRAI Keiji Tokyo Medical and Dental University, Associate Professor, 難治疾患研究所, 助教授 (70156628)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥3,800,000 (Direct Cost: ¥3,800,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2004: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | orexin / non-REM sleep / REM sleep / wakefulness / narcolepsy / histamine / 睡眠覚醒調節 / モチリン / 脳 / 腸神経系 / ラット / モルモット / 睡眠 / 脳波 |
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| Research Abstract |
Orexins A and B are novel neuropeptides which are known to be regulated in the control of feeding and arousal state. Recent studies showed that canine narcolepsy is caused by a deficit in the orexin 2 receptor (OX2R) gene, and that prepro-orexin knockout mice exhibited similar behavior to human and canine narcoleptics. Orexin-containing neurons are localized in the lateral hypothalamic area and densely project to the monoaminergic locus coeruleus, dopaminergic ventral tegmental area, serotonergic dorsal raphe nuclei and histaminergic tuberomammillary nucleus. An intracerebroventricular (ICV) infusion of orexin A and orexin B induced significant arousal effects in freely behaving rats. Hence, brain vigilance state seems to be regulated by the orexin network systems. Orexin A co-administration with pyrilamine significantly inhibited the effects of orexin A-induced wakefulness. Since direct synaptic connectivity from orexin nerve terminals to histaminergic neurons in the tuberomammillary
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nucleus (TMN) where the OX_2R is abundantly expressed, we investigated the effects of intraperitoneal (ip) injection of alpha-fluoromethylhistidine (FMH), a histamine synthesis inhibitor, on orexin-induced wakefulness in rats. Pretreatment with alpha-FMH, significantly inhibited the orexin B-induced wakefulness in rats. This study therefore suggests that arousal state regulation by orexin neurons is mediated through the histaminergic system in the TMN. Furthermore, we have determined the arousal effects of newly developed selective orexin receptor type 2 agonist, [Ala^<11>]orexin-B, on the sleep-wake cycle in rats. The effects of ICV infusion of [Ala^<11>]orexin-B (1,10 and 40 nmol) during the light period dose-dependently resulted in a significant increase in wake duration and a significant decrease in rapid eye movement (REM) and non-REM sleep. The efficacy of [Ala^<11>]orexin-B was comparable to that of native peptides at the same dose. These findings suggest that orexin receptor type 2 plays an important role in the modulation of sleep-wake state and behavioral responses. Less
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