Behavioral and Systems Neuroscience Program, Department of Psychology, Rutgers University New Brunswick, NJ, USA.
Front Cell Neurosci. 2013 Oct 8;7:173. doi: 10.3389/fncel.2013.00173.
The neuropeptide, orphanin FQ/nociceptin (OFQ/N or simply, nociceptin), is expressed in both neuronal and non-neuronal tissue, including the immune system. In the brain, OFQ/N has been investigated in relation to stress, anxiety, learning and memory, and addiction. More recently, it has also been found that OFQ/N influences glial cell functions, including oligodendrocytes, astrocytes, and microglial cells. However, this latter research is relatively small, but potentially important, when observations regarding the relationship of OFQ/N to stress and emotional functions is taken into consideration and integrated with the growing evidence for its involvement in cells that mediate inflammatory events. This review will first provide an overview and understanding of how OFQ/N has been implicated in the HPA axis response to stress, followed by an understanding of its influence on natural and learned anxiety-like behavior. What emerges from an examination of the literature is a neuropeptide that appears to counteract anxiogenic influences, but paradoxically, without attenuating HPA axis responses generated in response to stress. Studies utilized both central administration of OFQ/N, which was shown to activate the HPA axis, as well as antagonism of NOP-R, the OFQ/N receptor. In contrast, antagonist or transgenic OFQ/N or NOP-R knockout studies, showed augmentation of HPA axis responses to stress, suggesting that OFQ/N may be needed to control the magnitude of the HPA axis response to stress. Investigations of behavior in standard exploratory tests of anxiogenic behavior (eg., elevated plus maze) or learned fear responses have suggested that OFQ/N is needed to attenuate fear or anxiety-like behavior. However, some discrepant observations, in particular, those that involve appetitive behaviors, suggest a failure of NOP-R deletion to increase anxiety. However, it is also suggested that OFQ/N may operate in an anxiolytic manner when initial anxiogenic triggers (eg., the neuropeptide CRH) are initiated. Finally, the regulatory functions of OFQ/N in relation to emotion-related behaviors may serve to counteract potential neuroinflammatory events in the brain. This appears to be evident within the glial cell environment of the brain, since OFQ/N has been shown to reduce the production of proinflammatory cellular and cytokine events. Given that both OFQ/N and glial cells are activated in response to stress, it is possible that there is a possible convergence of these two systems that has important repercussions for behavior and neuroplasticity.
孤啡肽（orphanin FQ/nociceptin，OFQ/N，简称孤啡肽）是一种神经肽，存在于神经元和非神经元组织中，包括免疫系统。在大脑中，孤啡肽已被研究与应激、焦虑、学习和记忆以及成瘾有关。最近，人们还发现孤啡肽影响神经胶质细胞的功能，包括少突胶质细胞、星形胶质细胞和小胶质细胞。然而，当考虑到孤啡肽与应激和情绪功能的关系的观察结果，并与越来越多的证据整合在一起，证明其参与介导炎症事件的细胞时，这方面的研究相对较少，但却很重要。本综述首先概述和理解孤啡肽如何参与 HPA 轴对应激的反应，然后理解其对自然和习得性焦虑样行为的影响。从文献研究中得出的结论是，一种神经肽似乎可以对抗焦虑作用，但矛盾的是，它不会减弱孤啡肽对应激产生的 HPA 轴反应。研究既使用了孤啡肽的中枢给药，孤啡肽的中枢给药被证明可以激活 HPA 轴，也使用了孤啡肽受体 NOP-R 的拮抗剂。相反，拮抗剂或转基因孤啡肽或 NOP-R 敲除研究表明，HPA 轴对应激的反应增强，这表明孤啡肽可能需要控制 HPA 轴对应激的反应幅度。在标准焦虑行为探索性测试（如高架十字迷宫）或习得性恐惧反应中的行为研究表明，孤啡肽需要减少恐惧或焦虑样行为。然而，一些不一致的观察结果，特别是那些涉及食欲行为的观察结果表明，NOP-R 缺失并不能增加焦虑。但是，也有人认为，当最初的焦虑触发因素（例如神经肽 CRH）启动时，孤啡肽可能以抗焦虑的方式发挥作用。最后，孤啡肽在与情绪相关的行为方面的调节功能可能有助于抵消大脑中潜在的神经炎症事件。这在大脑的神经胶质细胞环境中是显而易见的，因为孤啡肽已被证明可以减少促炎细胞和细胞因子事件的产生。由于孤啡肽和神经胶质细胞都对应激作出反应，因此这两种系统可能会发生融合，这对行为和神经可塑性有重要影响。
