The Nociceptin System in Inflammation and Sepsis

Nociceptin/OrphaninFQ, N/OFQ, and its receptor NOP represent a non-opioid branch of the opioid family. There is growing interest in the involvement of this system during inflammation and sepsis as it is present in immune cells and modifies immunocyte function. Systemic N/OFQ increased mortality in an animal model of sepsis and there is limited evidence for increased plasma N/OFQ in patients with sepsis who died compared to those who survived. This thesis explores changes in the expression of NOP and ppN/OFQ-mRNA by polymorphs (PMN) and of N/OFQ peptide in plasma during inflammation and sepsis. A further aim was to investigate the relationship between the N/OFQ system with physiological and biochemical indicators of severity of disease. Forty patients undergoing cardiopulmonary bypass (CPB) and 49-patients with sepsis in the Intensive Care Unit (ICU) were recruited into 2-studies. In the CPB study we observed a 57% reduction of NOP-mRNA and a 95% reduction of ppN/OFQ-mRNA expression in PMN. Plasma N/OFQ concentrations increased by over 30%. Higher plasma N/OFQ was associated with lower NOP-mRNA. These changes were related to prolonged aortic cross clamp time. In patients with sepsis there was an 85% reduction of ppN/OFQ-mRNA expression compared to a sample taken after recovery from sepsis. Lower expression of ppN/OFQ-mRNA was associated with increased inotropic support and lactate concentrations on the first day of sepsis. Our data did not show any differences amongst survivors and non-survivors. During inflammation(CPB) and sepsis there was reduced expression of NOP and ppN/OFQ-mRNA with an inverse relationship between plasma N/OFQ(CPB study) and NOP-mRNA expression, suggestive of a possible feedback mechanism. Based on the current evidence (this thesis and literature) we suggest that N/OFQ could contribute to the complex pathophysiological process occurring during inflammation and sepsis and warrant further study.