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はじめに
ナルコレプシーは1880年,フランスのGelineau19)によって初めて記載された睡眠覚醒障害で,現在では比較的まとまった疾患単位として捉えられており,一般人口における有病率は0.02%から0.05%と報告されている63)。1956年,YossとDaly81)によって,ナルコレプシーの以下の4つの基本症状が明らかにされた。1)睡眠発作,傾眠傾向:昼間眠りやすく,しばしば耐えがたい眠気におそわれて眠り込む。2)カタプレキシー:笑う,怒るなどの情動を契機として起こる,全身または部分的な短時間の脱力状態で,意識消失は伴わない。3)入眠時幻覚:寝入りばなに起こる鮮明で現実感,覚醒感のある幻覚。4)睡眠麻痺:入眠時に起こる脱力状態で覚醒感があり,しばしば入眠時幻覚を伴う。1963年,睡眠ポリグラフィーによる研究によって,この疾患では覚醒から睡眠の移行が,しばしばREM睡眠で始まる(sleep-onset REM periods;SOREMP)ということが指摘されて以来69),カタプレキシー,入眠時幻覚,睡眠麻痺は,この疾患に特徴的な入眠時REM睡眠期の特殊型とみなされ,今日ではこれら3症状をまとめてREM睡眠関連症状とも呼び,REM睡眠の過程が解離した形ないしは部分的に出現した現象であると理解されている79)。
1984年,本多ら27,31)により,ヒト・ナルコレプシーでは,白血球クラスII抗原であるHLA-DR2,DQW6がほぼ100%陽性であることが報告され,ナルコレプシーの病因解明の新たな糸口になると注目されたが,未だこの疾患の病因は不明である。現在までのところ,ナルコレプシーでは,粗大な脳器質病変は見出されず15),睡眠覚醒,とくにREM睡眠の発現機構に関連した微細な神経伝達物質の異常,あるいは神経回路の異常が推定されている。その解明には睡眠覚醒機序,とくにREM睡眠中に生じる神経生理学的機構を明らかにすることが必要であり,病態生理の理解,とくに病因の解明には,臨床研究はもちろんのこと,適切な動物モデルを用いることがきわめて有用と思われる。通常,疾患の動物モデルには,実験発症モデルと自然発症モデルとがあるが,実験発症モデルとして脳局所破壊や薬物注入によるナルコレプシーのモデルも数々試みられたが,ヒト・ナルコレプシーとの類似性においてはいずれも満足のいくものではなかった13,50)。1973年,アメリカの獣医Kenechtらにより,ナルコレプシーの自然発症モデル,すなわちイヌのナルコレプシー(Dachshund)が発見された37)。その後,Stanford大学精神科睡眠障害センターが遺伝性ナルコレプシー犬(Doberman pinscher,Labrador retriever)を集め,繁殖コロニーを作って研究を進めてきたが,これらはヒトのナルコレプシーときわめて類似性の高いものであり,治療薬のスクリーニングのみならずREM睡眠の発現機構,ナルコレプシーの病因解明に迫りうる貴重な存在と考えられている4,50~52)。
Canine narcolepsy is a genetically transmitted animal model of human narcolepsy, a disorder of rapid eye movement (REM) sleep characterized by excessive daytime sleepiness and cataplexy (dramatic episodes of muscle weakness induced by emotions). The elucidation of the mechanisms involved in cataplexy is very closely linked to the understanding of REM sleep and the muscle atonia normally present during this sleep stage. Narcoleptic dogs have been extensively used in vivo and in vitro to investigate the pathophysiology of narcolepsy and to elaborate new therapeutic strategies for human narcolepsy.
The importance of pontine cholinergic systems in REM sleep regulation has been well established by both in vivo pharmacology and experiments involving the local stimulation of selective brainstem regions. In canine narcolepsy, central muscarinic stimulation with physostigmine increases cataplexy, while cholinergic blockade with atropine improves cataplexy. This pharmacological result suggests that a central cholinergic mechanism is involved in the control of cataplexy in canine narcolepsy. In addition to the cholinergic mechanisms, central monoaminergic mechanisms have been thought to be involved in REM sleepregulation and narcolepsy. Antidepressant drugs (monoamine uptake blockers) and amphetamine-like compounds (monoamine releasing agents) are treatments of choice for human narcolepsy and are also very potent at reducing canine cataplexy. However, these two classes of drugs are pharmacologically very non-specific, and globally act to increase monoamine levels (norepinephrine, dopamine, and serotonin) in the synaptic cleft. These global pharmacological effects on monoaminergic mechanisms needed to be more specifically investigated by using drugs selective for a single monoamine and, if possible, for individual postsynaptic receptors. We therefore explored the effect on canine cataplexy of various compounds selective for the noradrenergic, dopaminergic, or serotonergic systems. Results to date clearly demonstrate a preferential involvement of norepinephrine over dopamine or serotonin. The most potent compounds reducing canine cataplexy are the noradrenergic uptake blockers (such as nisoxetine), the alpha-1 agonists (such as methoxamine) or the alpha-2 antagonists (such as yohimbine), whereas the alpha-1 antagonists (such as prazosin) and some alpha-2 agonists (such as BHT-920) are extremely potent cataplexy-inducing compounds. Alpha-2 receptors are known to be located pre- and post-synaptically and it is difficult to infer if either or both site(s) are implicated in the observed effect above. We, however, favor the interpretation that the effects of alpha-2 compounds on cataplexy are mediated through presynaptic alpha-2 receptors (which are involved in the autoinhibition of norepinephrine release) since alpha-2 blockade mimics the effects of alpha-1 stimulation (arousal and decrease in cataplexy), whereas alpha-2 stimulation with BHT-920 reproduces the effect of alpha-1 antagonists (decrease in arousal and increase in cataplexy) in the canine model. These results all suggest that noradrenergic mechanisms are inhibitory to REM sleep and cataplexy, and that the final common pathway involves a postsynaptic alpha-1 receptor. Based on this pharmacological evidence, studies of alpha adrenoceptor levels and affinities in various brain areas of narcoleptic and control dogs were conducted. The most notable findings of these receptor studies were a selective increase in alpha-1 adrenergic receptors in the amygdala and an increase of alpha-2 receptors in the locus coeruleus" in narcoleptic dogs, compared to breed and age matched controls.
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