Department of Neuroscience, Retzius väg 8, S-171 77 Stockholm, Sweden.
Department of Pharmacology & Therapeutics Faculty of Medicine & Health Sciences UAE University, Al Ain, UAE; Department of Neuroscience, Retzius väg 8, S-171 77 Stockholm, Sweden.
Eur Neuropsychopharmacol. 2017 Dec;27(12):1298-1307. doi: 10.1016/j.euroneuro.2017.09.005. Epub 2017 Nov 6.
The endogenous neuropeptide nociceptin (N/OFQ), which mediates its actions via the nociceptin receptor (NOP), is implicated in multiple behavioural and physiological functions. This study examined the effects of the NOP agonists N/OFQ and the synthetic agonist Ro 64-6198, the antagonists NNN and NalBzoH, as well as deletion of the Pronociceptin gene on emotional memory in mice. The animals were tested in the passive avoidance (PA) task, dependent on hippocampal and amygdala functions. N/OFQ injected intraventricularly (i.c.v.) prior to training produced a biphasic effect on PA retention; facilitation at a low dose and impairment at higher doses. Ro 64-6198 also displayed a biphasic effect with memory facilitation at lower doses and impairment at a high dose. None of the agonists influenced PA training latencies. NNN did not significantly modulate retention in the PA task but antagonized the inhibitory effects of N/OFQ. NalBzoH facilitated memory retention in a dose-dependent manner and blocked the impairing effects of N/OFQ. However, neither NNN nor NalBzoH blocked the memory-impairing effects of Ro 64-6198. Finally, the Pnoc knockout mice exhibited enhanced PA retention latencies compared to the wild type mice. The biphasic effect of the natural ligand and Ro 64-6198 and the failure of the antagonists to block the action of Ro 64-6198 indicate complexity in ligand-receptor interaction. These results indicate that brain nociceptin and its NOP has a subtle role in regulation of mechanisms of relevance for treatment of disorders with processing disturbances of aversive events e.g. Alzheimer's disease, anxiety, depression and PTSD.
内源性神经肽孤啡肽（N/OFQ）通过孤啡肽受体（NOP）发挥作用，与多种行为和生理功能有关。本研究探讨了 NOP 激动剂 N/OFQ 和合成激动剂 Ro 64-6198、拮抗剂 NNN 和 NalBzoH 以及 Pronociceptin 基因缺失对小鼠情绪记忆的影响。动物在被动回避（PA）任务中进行测试，该任务依赖于海马和杏仁核的功能。N/OFQ 脑室注射（i.c.v.）在训练前产生了对 PA 保留的双相作用；低剂量促进，高剂量损害。Ro 64-6198 也表现出双相作用，低剂量记忆促进，高剂量损害。没有一种激动剂影响 PA 训练潜伏期。NNN 对 PA 任务的保留没有显著影响，但拮抗了 N/OFQ 的抑制作用。NalBzoH 以剂量依赖性方式促进记忆保留，并阻断了 N/OFQ 的损害作用。然而，NNN 和 NalBzoH 都不能阻断 Ro 64-6198 的记忆损害作用。最后，Pnoc 敲除小鼠与野生型小鼠相比，PA 保留潜伏期更长。天然配体和 Ro 64-6198 的双相作用以及拮抗剂不能阻断 Ro 64-6198 的作用表明配体-受体相互作用的复杂性。这些结果表明，大脑孤啡肽及其 NOP 在调节与处理厌恶事件有关的机制方面发挥着微妙的作用，例如阿尔茨海默病、焦虑、抑郁和 PTSD 等疾病。
