Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients

Stamer, Ulrike; Book, Marius; Comos, C.; Zhang, L.; Nauck, Friedemann; Stüber, Frank

doi:10.1093/bja/aer007

Cited by 23 publications

(30 citation statements)

References 29 publications

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“…For HPRT, 16 nM of universal probe #73 (Roche, Mannheim, Germany), 4 µl LightCycler® TaqMan® Master (Roche, Mannheim, Germany) and 10 pmol of each primer (TIB MOLBIOL, Berlin, Germany) were used. The sequence of primers and PCR conditions have been described previously [7], [10], [19]. Primer sequences were as follows: HPRT, 5′-TGACCTTGATTTATTTTGCATACC-3′ and 5′-CGAGCAAGACGTTCAGTCCT-3′; NOP, 5′-TGCCGTTCTGGGAGGTTATCTA-3′ and 5′-TTAGGGTGAAGGTGCTGGTGA-3′; PNoc, 5′-CCTGCACCAGAATGGTAATG-3′ and 5′-GCTGAGCACATGCTGTTTG-3′.…”

Section: Methodsmentioning

confidence: 99%

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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Section: Methodsmentioning

confidence: 99%

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

2013

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“…Stamer et al (23) found lower pN/OFQ expression in the peripheral blood cells (PBC) of end-stage cancer patients and septic patients compared with healthy controls. They also showed that increased plasma procalcitonin, a marker of infl ammation, was associated with decreased pN/OFQ in all patient groups.…”

Section: Discussionmentioning

confidence: 99%

Decreased plasma nociceptin/orphanin FQ levels after acute coronary syndromes

Csobay-Novák

Sótonyi

Krepuska

et al. 2012

Acta Physiologica Hungarica

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Foregoing researches made on the N/OFQ system brought up a possible role for this system in cardiovascular regulation. In this study we examined how N/OFQ levels of the blood plasma changed in acute cardiovascular diseases. Three cardiac patient groups were created: enzyme positive acute coronary syndrome (EPACS, n = 10), enzyme negative ACS (ENACS, n = 7) and ischemic heart disease (IHD, n = 11). We compared the patients to healthy control subjects (n = 31). We found signifi cantly lower N/OFQ levels in the EPACS [6.86 (6.21-7.38) pg/ ml], ENACS [6.97 (6.87-7.01) pg/ml and IHD groups [7.58 (7.23-8.20) pg/ml] compared to the control group [8.86 (7.27-9.83) pg/ml]. A signifi cant correlation was detected between N/OFQ and white blood cell count (WBC), platelet count (PLT), creatine kinase (CK), glutamate oxaloacetate transaminase (GOT) and cholesterol levels in the EPACS group.Decreased plasma N/OFQ is closely associated with the presence of acute cardiovascular disease, and the severity of symptoms has a signifi cant negative correlation with the N/OFQ levels. We believe that the rate of N/OFQ depression is in association with the level of ischemic stress and the following infl ammatory response. Further investigations are needed to clarify the relevance and elucidate the exact effects of the ischemic stress on the N/OFQ system. Keywords: acute coronary syndrome, angina pectoris, nociceptin/orphanin FQ, ischemic stressMore than a decade now that a new chapter has been opened in the research of the opioid system with Mollereau cloning a new member of the opioid receptor family, which was named opioid receptor like orphan receptor (ORL-1) because it was reminiscent of the opioid receptors on both structural and functional ground (21). A year later the endogenous ligand of the ORL-1 was identifi ed and named nociceptin (for its hyperalgesic effect on mice when administered intracerebroventricularly) and orphanin-FQ, because of the Phe and Gln amino acids on the ends of the peptide chain (21, 22). The ORL-1 receptor was renamed NOP receptor and the nociceptin/orphanin FQ peptide as N/OFQ in the current nomenclature by NC-IUPHAR.

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“…However, when evaluating the role of N/OFQ-NOP receptor system in a complex event such as sepsis, we should be aware of the broad range of effects evoked by NOP receptor signaling, that contribute to the septic condition, such as impairment of cardiovascular performance and tissue perfusion, beside the immune responses herein discussed (for a review see [57]). Very recently, Stamer and colleagues [58] have shown that peripheral blood cells from patients with sepsis had higher N/OFQ and lower ppN/OFQ mRNA expression than healthy controls. Again, these observations suggest the involvement of the NOP-N/OFQ system in inflammation and impaired immune function in sepsis.…”

Section: N/ofq-nop Receptor System and Inflammatory And Autoimmunementioning

confidence: 99%

“…Anton and colleagues [43] showed that N/OFQ inhibits antibody formation in a naloxone-insensitive manner, thus suggesting that N/OFQ effects, at least in this particular case, are not mediated by classical opioid receptors [43]. Another recent evidence that show no interaction between N/OFQ-NOP receptor system and the classic opioid system is coming from a clinical study, in which patients suffering from cancer who were taking opioid medication (morphine or equivalents) did not display any significant alterations in NOP and ppN/OFQ expression compared with those who did not receive opioids pretreatment [58]. These observations suggest that, despite the immunosuppressive effects of opioid in addicted patients [110], the mechanisms by which classical opioids affect immune functions, especially in the periphery, did not seem to be related to the N/OFQ-NOP receptor system.…”

Section: Relationship Between N/ofq and Classical Opioids In The Rmentioning

confidence: 99%

NOP Receptor Ligands as Potential Agents for Inflammatory and Autoimmune Diseases

Gavioli

Romão

2011

Journal of Amino Acids

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Nociceptin/orphanin FQ (N/OFQ) is a seventeen-amino acid peptide that is the endogenous ligand of a G-protein-coupled receptor (NOP). Various immune cells express the precursor protein and secrete N/OFQ as well as display binding sites for this peptide. The functional capacity of NOP receptor was demonstrated in vitro and in vivo studies by the ability of N/OFQ to induce chemotaxis of immune cells, to regulate the expression of cytokines and other inflammatory mediators, and to control cellular and humoral immunity. In this context, N/OFQ could modulate the outcome of some inflammatory diseases, such as sepsis and autoimmune pathologies by mechanisms not clearly elucidated yet. In fact, human body fluid revealed increased levels of N/OFQ under sepsis, arthritis, and Parkinson's diagnose. Preclinical studies pointed to the blockade of NOP receptor signaling as successful in treating these experimental conditions. Further preclinical and clinical studies are required to investigate the potential of NOP ligands in treating inflammatory diseases.

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Expression of the nociceptin precursor and nociceptin receptor is modulated in cancer and septic patients

Cited by 23 publications

References 29 publications

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

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

Decreased plasma nociceptin/orphanin FQ levels after acute coronary syndromes

NOP Receptor Ligands as Potential Agents for Inflammatory and Autoimmune Diseases

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