Orphanin FQ acts as an anxiolytic to attenuate behavioral responses to stress

Orphanin FQ (OFQ, Nociceptin) is a recently discovered 17-amino acid neuropeptide that is structurally related to the opioid peptides but does not bind opioid receptors. OFQ has been proposed to act as an anti-opioid peptide, but its widespread sites of action in the brain suggest that it may have more general functions. Here we show that OFQ plays an important role in higher brain functions because it can act as an anxiolytic to attenuate the behavioral inhibition of animals acutely exposed to stressful/anxiogenic environmental conditions. OFQ anxiolytic-like effects were consistent across several behavioral paradigms generating different types of anxiety states in animals (light-dark preference, elevated plus-maze, exploratory behavior of an unfamiliar environment, pharmacological anxiogenesis, operant conflict) and were observed at low nonsedating doses (0.1–3 nmol, intracerebroventricular). Like conventional anxiolytics, OFQ interfered with regular sensorimotor function at high doses (>3 nmol). Our results show that an important role of OFQ is to act as an endogenous regulator of acute anxiety responses. OFQ, probably in concert with other major neuropeptides, exerts a modulatory role on the central integration of stressful stimuli and, thereby, may modulate anxiety states generated by acute stress.

孤啡肽FQ（Orphanin FQ, OFQ, Nociceptin）是新近发现的17个氨基酸残基的神经肽，其结构与阿片肽类具有相似性，但无法结合阿片受体。此前有研究提出OFQ可作为抗阿片肽发挥作用，但其脑内广泛的作用位点提示其可能具备更为广谱的生理功能。本研究证实，OFQ可作为抗焦虑剂（anxiolytic）缓解急性暴露于应激性/致焦虑性环境条件下动物的行为抑制反应，因此在高级脑功能中发挥重要作用。

OFQ的类抗焦虑效应在多种可诱发动物不同焦虑状态的行为学范式中均得到验证，包括明暗箱偏好实验、高架十字迷宫、陌生环境探索行为、药物诱导焦虑模型以及操作性冲突实验，且该效应在低剂量（0.1~3纳摩尔，脑室内给药）且无镇静作用的条件下即可观测到。与传统抗焦虑药物类似，当给药剂量高于3纳摩尔时，OFQ会干扰动物正常的感觉运动功能。

本研究结果表明，OFQ的重要生理功能之一是作为急性焦虑应答的内源性调节因子。OFQ或可与其他主要神经肽协同作用，对应激刺激的中枢整合过程发挥调控作用，进而调节急性应激诱发的焦虑状态。