Behavioral Pharmacology Laboratory, Department of Biophysics and Pharmacology, Federal University of Rio Grande do Norte, Natal, Brazil.
Department of Chemistry and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy.
J Psychopharmacol. 2019 Dec;33(12):1540-1549. doi: 10.1177/0269881119864942. Epub 2019 Jul 24.
The peptide nociceptin/orphanin FQ (N/OFQ) and its receptor (NOP) are implicated in the modulation of emotional states. Previous human and rodent findings support NOP antagonists as antidepressants. However, the role played by the N/OFQ-NOP receptor system in resilience to stress is unclear.
The present study investigated the effects of activation or blockade of NOP receptor signaling before exposure to acute stress.
The behavioral effects of the administration before stress of the NOP agonists Ro 65-6570 (0.01-1 mg/kg) and MCOPPB (0.1-10 mg/kg), and the NOP antagonist SB-612111 (1-10 mg/kg) were assessed in mice exposed to inescapable electric footshock and forced swim as stressors. The behavioral phenotype of mice lacking the NOP receptor (NOP(-/-)) exposed to inescapable electric footshock was also investigated.
The activation of NOP receptor signaling with the agonists increased the percentage of mice developing helpless behavior and facilitated immobile posture. In contrast, the blockade of NOP receptor reduced the acquisition of depressive-like phenotypes, and similar resistance to develop helpless behaviors was observed in NOP(-/-) mice. Under the same stressful conditions, the antidepressant nortriptyline (20 mg/kg) did not change the acquisition of helpless behavior and immobile posture.
These findings support the view that NOP activation during acute stress facilitates the development of depressive-related behaviors, whereas NOP blockade has a protective outcome. This study showed for first time that NOP antagonists are worthy of investigation as preemptive treatments in patients with severe risk factors for depression.
孤啡肽（nociceptin/orphanin FQ，N/OFQ）及其受体（NOP）参与情绪状态的调节。先前的人类和啮齿动物研究结果支持 NOP 拮抗剂作为抗抑郁药。然而，N/OFQ-NOP 受体系统在应激抵抗中的作用尚不清楚。
本研究在暴露于急性应激之前，研究了激活或阻断 NOP 受体信号对 NOP 受体信号的影响。
在暴露于不可逃避的电击和强迫游泳等应激源之前，给予 NOP 激动剂 Ro 65-6570（0.01-1mg/kg）和 MCOPPB（0.1-10mg/kg）以及 NOP 拮抗剂 SB-612111（1-10mg/kg），评估其对小鼠的行为影响。还研究了缺乏 NOP 受体（NOP(-/-)）的小鼠暴露于不可逃避的电击后的行为表型。
激动剂激活 NOP 受体信号增加了出现无助行为的小鼠百分比，并促进了不动姿势。相反，NOP 受体阻断减少了抑郁样表型的获得，并且在 NOP(-/-)小鼠中也观察到类似的抵抗无助行为的能力。在相同的应激条件下，抗抑郁药米氮平（20mg/kg）并没有改变无助行为和不动姿势的获得。
这些发现支持这样一种观点，即急性应激期间 NOP 的激活促进了与抑郁相关的行为的发展，而 NOP 阻断具有保护作用。本研究首次表明，NOP 拮抗剂作为有严重抑郁风险因素的患者的预防性治疗值得进一步研究。
