Nociceptin/orphanin FQ in inflammation and sepsis

Serrano-Gomez, A; Thompson, Jonathan P.; Lambert, David G.

doi:10.1093/bja/aeq337

Cited by 28 publications

(23 citation statements)

References 56 publications

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“…The effects of N/OFQ are not limited to the CNS. In peripheral tissues N/OFQ produces antitussive effects, negative chronotropic and ionotripic effects on heart, vasodilation, inhibition of gastrointestinal motility, inflammation, and sepsis (Lambert, 2008; Armstead, 2011; Leggett et al, 2009; Serrano-Gomez et al, 2011). However, at present a dearth of data from human clinical studies exists that have explored modification of these disease processes following manipulation of the N/OFQ system.…”

Section: Introductionmentioning

confidence: 99%

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

Witkin

Statnick

Rorick-Kehn

et al. 2014

Pharmacology & Therapeutics

179

162

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Nociceptin/Orphanin FQ (N/OFQ) is a 17 amino acid peptide that was deorphanized in 1995. The generation of specific agonists, antagonists and receptor deficient mice and rats has enabled progress in elucidating the biological functions of nociceptin. In addition, radio-imaging technologies have been advanced for investigation of this system in animals and humans. Together with traditional neurobehavioral techniques, these tools have been utilized to identify the biological significance of the N/OFQ system and its interacting partners. The present commentary focuses on the role of N/OFQ in the regulation of feeding and body weight homeostasis, stress and the stress-related psychiatric disorders of depression and anxiety, and in drug and alcohol dependence. Critical evaluation of the current scientific preclinical literature suggests that small molecule modulators of nociceptin opioid peptide receptors (NOP) might be useful in the treatment of diseases related to these biological functions. In particular, the literature data suggest that antagonism of NOP receptors will produce anti-obesity and antidepressant activities in humans. However, there are also contradictory data discussed. The current literature on the role of N/OFQ in anxiety and addiction, on the other hand points primarily to a role of agonist modulation being potentially therapeutic. Some drug-like molecules that function either as agonists or antagonists of NOP receptors have been optimized for human clinical study to test some of these hypotheses. The discovery of PET ligands for NOP receptors, combined with the pharmacological tools and burgeoning preclinical data set discussed here bodes well for a rapid advancement of clinical understanding and potential therapeutic benefit.

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Section: Introductionmentioning

confidence: 99%

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

Witkin

Statnick

Rorick-Kehn

et al. 2014

Pharmacology & Therapeutics

179

162

View full text Add to dashboard Cite

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“…That is, subsequent to the induction of sepsis by cecal ligation and puncture, OFQ/N administration to rats increased mortality, while NOP-R antagonist treatment attenuated various cellular and cytokine parameters of inflammation, and reduced mortality (Carvalho et al, 2008). Corresponding data in human clinical situations has been noted, with higher correlations of plasma OFQ/N in non-surviving septic patients suggesting that antagonism of OFQ/N may be a potential immunotherapeutic manipulation that may aid recovery (Serrano-Gomez et al, 2011). Overall, while little is known about the precise interactions between OFQ/N and the immune system, there is compelling evidence to explore this relationship further and elucidate the relevance of this to immunopathological and inflammatory disorders.…”

Section: Ofq/n and Inflammationmentioning

confidence: 81%

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

Mallimo

Kusnecov

2013

Front. Cell. Neurosci.

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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.

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“…Both in vitro and in vivo studies have supported the evidence that NOP and nociceptin play a role in systemic inflammatory reactions and sepsis [11]. However, studies in humans have been conflictual: Decreased nociceptin plasma protein has been reported in fibromyalgia-syndrome patients compared to controls [9].…”

Section: Discussionmentioning

confidence: 94%

Inflammatory Mediators Influence the Expression of Nociceptin and Its Receptor in Human Whole Blood Cultures

2013

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BackgroundNociceptin/orphanin FQ and its receptor (NOP) are involved in immune responses, inflammation and pain processing. The aim of this study was to investigate the modulation of NOP and prepro-nociceptin (PNoc), the precursor of nociceptin, by inflammatory mediators in human whole blood.MethodsPeripheral blood from healthy volunteers was cultured for 0, 3, 6 and 24 hrs with or without lipopolysaccharide (LPS), tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-10 or interferon (IFN)-γ. NOP and PNoc mRNA of peripheral white blood cells were detected by quantitative RT-PCR. Cytokine concentrations in supernatants of whole blood cultures were measured using ELISA. In addition, an intervention experiment using anti-cytokine antibodies was conducted to evaluate possible mechanisms involved in the modulation of NOP and PNoc by LPS. The primary goal was to investigate NOP and PNoc mRNA expression in human peripheral blood under inflammatory conditions.ResultsLPS significantly suppressed NOP (median area under the mRNA-expression-time curve (1st/3rd quartile): 5.4 (4.6/6.6) normalized ratio · hr) and PNoc expression (40.8 (34.4/49.5)) compared to baseline measures (NOP: 22.7 (17.1/25.3); PNoc: 69.9 (58.4/89.2), both p<0.001). LPS incubation induced cytokine concentrations (TNF-α, IL-1β, IL-10 and IFN-γ) in whole blood cultures. Incubation with TNF-α, IL-1β, IL-10 or IFN-γ decreased NOP mRNA levels to varying extents (p<0.05 for all). In contrast, PNoc mRNA expression was decreased by IL-10 only (p = 0.018). The LPS effect on NOP expression could be antagonized by anti-TNF-α and anti-IL-1β, whereas anti-IL-10 and anti-INF-γ had no effect. There was no change of PNoc expression when LPS induced cytokines were antagonized by the respective antibodies.ConclusionsLPS as well as cytokines suppress mainly NOP and, in part, PNoc mRNA expression in human whole blood cultures. This may represent a negative feedback loop to the previously described upregulation of cytokines by PNoc.

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Nociceptin/orphanin FQ in inflammation and sepsis

Cited by 28 publications

References 56 publications

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

The biology of Nociceptin/Orphanin FQ (N/OFQ) related to obesity, stress, anxiety, mood, and drug dependence

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

Inflammatory Mediators Influence the Expression of Nociceptin and Its Receptor in Human Whole Blood Cultures

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