Background And ObjectivesNociceptin/Orphanin FQ (N/OFQ) is a non-classical endogenous opioid peptide that modulates immune function in vitro. Its importance in inflammation and human sepsis is unknown. The objectives of this study were to determine the relationship between N/OFQ, transcripts for its precursor (pre-pro-N/OFQ [ppNOC]) and receptor (NOP), inflammatory markers and clinical outcomes in patients undergoing cardiopulmonary bypass and with sepsis.MethodsA prospective observational cohort study of 82 patients admitted to Intensive Care (ICU) with sepsis and 40 patients undergoing cardiac surgery under cardiopulmonary bypass (as a model of systemic inflammation). Sixty three healthy volunteers, matched by age and sex to the patients with sepsis were also studied. Clinical and laboratory details were recorded. Polymorph ppNOC and NOP receptor mRNA were determined using quantitative PCR. Plasma N/OFQ was determined using ELISA and cytokines (TNF- α, IL-8, IL-10) measured using radioimmunoassay. Data from patients undergoing cardiac surgery were recorded before, 3 and 24 hours after cardiopulmonary bypass. ICU patients with sepsis were assessed on Days 1 and 2 of ICU admission, and after clinical recovery.Main ResultsPlasma N/OFQ concentrations increased (p<0.0001) on Days 1 and 2 of ICU admission with sepsis compared to matched recovery samples. Polymorph ppNOC (p= 0.019) and NOP mRNA (p<0.0001) decreased compared to healthy volunteers. TNF-α, IL-8 and IL-10 concentrations increased on Day 1 compared to matched recovery samples and volunteers (p<0.0001). Similar changes (increased plasma N/OFQ, [p=0.0058], decreased ppNOC [p<0.0001], increased IL-8 and IL-10 concentrations [both p<0.0001]) occurred after cardiac surgery but these were comparatively lower and of shorter duration.ConclusionsThe N/OFQ system is modulated in ICU patients with sepsis with similar but reduced changes after cardiac surgery under cardiopulmonary bypass. Further studies are required to clarify the role of the N/OFQ system in inflammation and sepsis, and the mechanisms involved.

Nociceptin/orphanin FQ, N/OFQ, and its receptor NOP represent a non-opioid branch of the opioid superfamily that were first studied for their effects on pain responses. Both N/OFQ and NOP are involved in a wide range of 'non-pain' responses including immunomodulation and cardiovascular control. There is now growing interest in this system in inflammation and sepsis, which is the focus of this review article. The N/OFQ-NOP system is present in immune cells and N/OFQ modifies immunocyte function. On the basis of various in vitro and in vivo studies, N/OFQ increases the inflammatory response in healthy anaesthetized animals and in those with a septic or inflammatory process. It affects tissue perfusion, increases capillary leakage and inflammatory markers, and leads to immune cell chemotaxis. Moreover, NOP activation produces bradycardia and hypotension. Systemic N/OFQ administration also increased mortality in an animal model of sepsis, and there is limited evidence for increased plasma N/OFQ concentrations in patients with sepsis who died compared with those who survived. There is a need for further observational and mechanistic studies in patients with established inflammatory processes or sepsis. These studies may facilitate the design of appropriate clinical studies to evaluate NOP ligands as modifiers of the inflammatory response.

The human right atrium of patients with coronary artery disease and heart failure expresses mRNA encoding NOP and possibly low levels of MOP. This does not correlate with degree of cardiac dysfunction. In addition, the atrium does not express ppN/OFQ mRNA.