Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism.
Orexin-1 receptor blockade dysregulates REM sleep in the presence of orexin-2 receptor antagonism.
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DOI：
10.3389/fnins.2014.00028
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发表时间：
2014
影响因子：
4.3
通讯作者：
Lovenberg TW
中科院分区：
文献类型：
--
作者：
Dugovic C;Shelton JE;Yun S;Bonaventure P;Shireman BT;Lovenberg TW
根据食欲素在通过激活食欲素-1（OX 1 R）和食欲素-2（OX 2 R）受体维持觉醒中的突出作用，各种双重OX 1/2 R拮抗剂已显示促进动物和人的睡眠。虽然选择性阻断OX 2 R似乎足以启动和延长睡眠，但额外抑制OX 1 R的有益作用仍存在争议。在大鼠中进一步研究了OX 1 R和OX 2 R对双重OX 1/2 R拮抗剂诱导的睡眠效应的相对贡献，特别是对快速眼动（REM）睡眠的贡献，因为基于临床和临床前数据，食欲素系统的缺乏与发作性睡病/癫痫相关。正如预期的那样，双重OX 1/2 R拮抗剂SB-649868在暗相开始时经口给药（10和30 mg/kg）后可有效促进非REM（NREM）和REM睡眠。然而，与NREM睡眠相比，REM睡眠的开始更明显地减少，REM/总睡眠比率显著增强，以及发生几次直接觉醒到REM睡眠过渡（REM侵入），证明了REM睡眠的中断。皮下给药时，OX 2 R拮抗剂JNJ-10397049（10 mg/kg）延长了NREM持续时间，而OX 1 R拮抗剂GSK-1059865（10 mg/kg）未改变睡眠。REM睡眠不受单独的OX 2 R或OX 1 R阻断剂的影响，但OX 1 R拮抗剂与OX 2 R拮抗剂联合给药诱导REM睡眠潜伏期显著缩短，REM睡眠持续时间增加，但NREM睡眠时间减少。这些结果表明，额外阻断OX 1 R至OX 2 R拮抗作用通过以NREM睡眠为代价改变平衡以有利于REM睡眠，从而导致REM睡眠失调，这可能增加不良事件的风险。这一假设的翻译仍有待于在临床上进行检验。
In accordance with the prominent role of orexins in the maintenance of wakefulness via activation of orexin-1 (OX1R) and orexin-2 (OX2R) receptors, various dual OX1/2R antagonists have been shown to promote sleep in animals and humans. While selective blockade of OX2R seems to be sufficient to initiate and prolong sleep, the beneficial effect of additional inhibition of OX1R remains controversial. The relative contribution of OX1R and OX2R to the sleep effects induced by a dual OX1/2R antagonist was further investigated in the rat, and specifically on rapid eye movement (REM) sleep since a deficiency of the orexin system is associated with narcolepsy/cataplexy based on clinical and pre-clinical data. As expected, the dual OX1/2R antagonist SB-649868 was effective in promoting non-REM (NREM) and REM sleep following oral dosing (10 and 30 mg/kg) at the onset of the dark phase. However, a disruption of REM sleep was evidenced by a more pronounced reduction in the onset of REM as compared to NREM sleep, a marked enhancement of the REM/total sleep ratio, and the occurrence of a few episodes of direct wake to REM sleep transitions (REM intrusion). When administered subcutaneously, the OX2R antagonist JNJ-10397049 (10 mg/kg) increased NREM duration whereas the OX1R antagonist GSK-1059865 (10 mg/kg) did not alter sleep. REM sleep was not affected either by OX2R or OX1R blockade alone, but administration of the OX1R antagonist in combination with the OX2R antagonist induced a significant reduction in REM sleep latency and an increase in REM sleep duration at the expense of the time spent in NREM sleep. These results indicate that additional blockade of OX1R to OX2R antagonism elicits a dysregulation of REM sleep by shifting the balance in favor of REM sleep at the expense of NREM sleep that may increase the risk of adverse events. Translation of this hypothesis remains to be tested in the clinic.
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DOI：
10.1073/pnas.1202526109
发表时间：
2012-09-25
影响因子：
11.1
作者：
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通讯作者：
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影响因子：
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