The role of orphanin FQ/nociceptin in neuroplasticity: relationship to stress, anxiety and neuroinflammation

Abstract

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.

Nociceptin and the nociceptin receptor in learning and memory

“…It is known that stress can alter N/OFQ-NOP receptor memory functions (Mallimo and Kusnecov, 2013). Thus, it is interesting that SR-8993 showed efficacy in preventing cued-fear memory consolidation in mice that had a previous traumatic stress exposure to immobilization to a wooden board (IMO) 6 days before being tested for cued-fear learning (Andero et al, 2013).…”

“…N/OFQ-NOP receptors are abundantly expressed in the central nervous system and peripheral organs, having different roles in several functions such as stress, immunology, depression, cardiovascular responses, drug abuse and anxiety (Bodnar, 2013; Gavioli and Calo, 2013; Mallimo and Kusnecov, 2013). In recent years the association between N/OFQ-NOP receptor and memory functions has gained considerable interest.…”

Involvement of the N/OFQ-NOP system in rat morphine antinociceptive tolerance: Are astrocytes the crossroad?

“…Moreover, astrocytes express NOP receptor and cytokine production by astrocytes can be inhibited by N/OFQ, an effect which represents one mechanism by which N/OFQ may reduce pain sensitivity (Fu et al, 2007). Furthermore, N/OFQ mRNA is increased in astrocytes treated with morphine (Takayama and Ueda, 2005), further, various proinflammatory cytokines as those increased during morphine treatment (eg., tumor necrosis factor and interleukin-1) can enhance astrocyte concentrations of immunoreactive N/OFQ and N/OFQ mRNA (Buzas et al, 2002; Mallimo and Kusnecov, 2013). In this view, our data suggest that lacking NOP receptor the ancillary role of N/OFQ in morphine antinociception is lost but losing the NOP-dependent astrocyte signal tolerance development may be delayed.…”

Sarı Kantaron (Hypericum Perforatum) ile Orfanin Etkileşiminin Depresyon Tedavisindeki Rolü

“…Bu opioid benzeri nöropeptid üzerine yapılan ilk çalışmalarda, Orfanin'in G protein reseptörüne seçici olarak bağlandığı; nosiseptin opioid benzeri peptid (NOP ) reseptörünün (ki bu ORL-1 veya orfan reseptör 1 olarakda adlandırılır); klasik opioid reseptörlere yapı olarak benzer olduğu fakat geleneksel opioid reseptörlere ilgisinin olmadığı (afinite) ve bağlanmadığı gösterilmiştir [26][27][28] . .…”

“…Ayrıca orfanin açık alana maruz kalma testi ve yükseltilmiş çoklu labirent gibi anksiyeteyi ölçen testlerde endokrin tepkilerin arttığı görülmüştür 39,41 . Aşağıdaki şekilde stresle indüklenen HPA ekseninde orfaninin etkisi verilmiştir 28 . …”