Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat
Blockade of Orexin-1 Receptors Attenuates Orexin-2 Receptor Antagonism-Induced Sleep Promotion in the Rat
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DOI：
10.1124/jpet.109.152009
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发表时间：
2009-07-01
影响因子：
3.5
通讯作者：
Lovenberg, Timothy W.
中科院分区：
文献类型：
--
作者：
Dugovic, Christine;Shelton, Jonathan E.;Lovenberg, Timothy W.
食欲素是由下丘脑外侧神经元产生的多肽，通过激活位于觉醒活性结构中的食欲素-1(OX1R)和食欲素-2(OX2R)受体，在维持觉醒中发挥重要作用。双氧合酶1/2R拮抗剂(2R)-2-[(1S)-6，7-dimethoxy-1-{2-[4-(trifluoromethyl)苯基]ethyl}-3，4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide(Almore Xant)对这两种受体的药理阻断已被证明在它们的活动期促进动物和人类的睡眠。然而，OX1R和OX2R在不同神经元回路中的选择性分布可能导致这两种受体在睡眠-觉醒调节中的不同影响。在选择性拮抗剂单独或联合治疗的大鼠中，评估OX1R和OX2R在睡眠中的作用与单胺释放的相关性。当在明/暗周期的任一个阶段给药时，氧合酶2受体拮抗剂1-(2，4-二溴苯基)-3-[(4S，5S)-2，2-二甲基-4-苯基-1，3-二恶烷-5-基]尿素(JNJ-10397049)缩短了持续睡眠的潜伏期，增加了非快速眼动和快速眼动睡眠时间。阿莫昔康的催眠活性较弱，而氧合酶1R拮抗剂1-(6，8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino)苯基]尿素(SB-408124)则没有任何作用。微透析研究表明，OX2R或OX1/2R拮抗剂降低了下丘脑外侧区细胞外组胺浓度，而OX1R和OX1/2R拮抗剂均增加了前额叶皮质的多巴胺释放。最后，OX1R与OX2R拮抗剂合用大大减弱了OX2R拮抗剂的催眠作用。这些结果表明，阻断OX2R足以启动和延长睡眠，这与组胺能系统失活的假设一致。另外，同时抑制OX1R可减弱选择性阻断OX2R所介导的促进睡眠的作用，这可能与多巴胺能神经传递有关。
Orexins are peptides produced by lateral hypothalamic neurons that exert a prominent role in the maintenance of wakefulness by activating orexin-1 (OX1R) and orexin-2 (OX2R) receptor located in wake-active structures. Pharmacological blockade of both receptors by the dual OX1/2R antagonist (2R)-2-[(1S)-6,7-dimethoxy-1-{2-[4-(trifluoromethyl) phenyl] ethyl}-3,4-dihydroisoquinolin-2(1H)-yl]-N-methyl-2-phenylethanamide (almorexant) has been shown to promote sleep in animals and humans during their active period. However, the selective distribution of OX1R and OX2R in distinct neuronal circuits may result in a differential impact of these receptors in sleep-wake modulation. The respective role of OX1R and OX2R on sleep in correlation with monoamine release was evaluated in rats treated with selective antagonists alone or in combination. When administered in either phase of the light/dark cycle, the OX2R antagonist 1-(2,4-dibromophenyl)-3-[(4S, 5S)-2,2-dimethyl-4-phenyl-1,3-dioxan-5-yl] urea (JNJ-10397049) decreased the latency for persistent sleep and increased nonrapid eye movement and rapid eye movement sleep time. Almorexant produced less hypnotic activity, whereas the OX1R antagonist 1-(6,8-difluoro-2-methylquinolin-4-yl)-3-[4-(dimethylamino) phenyl] urea (SB-408124) had no effect. Microdialysis studies showed that either OX2R or OX1/2R antagonism decreased extracellular histamine concentration in the lateral hypothalamus, whereas both OX1R and OX1/2R antagonists increased dopamine release in the prefrontal cortex. Finally, coadministration of the OX1R with the OX2R antagonist greatly attenuated the sleep-promoting effects of the OX2R antagonist. These results indicate that blockade of OX2R is sufficient to initiate and prolong sleep, consistent with the hypothesis of a deactivation of the histaminergic system. In addition, it is suggested that simultaneous inhibition of OX1R attenuates the sleep-promoting effects mediated by selective OX2R blockade, possibly correlated with dopaminergic neurotransmission.