NOP Receptor Ligands as Potential Agents for Inflammatory and Autoimmune Diseases

Abstract

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.

Nociceptin system as a target in sepsis?

“…55 Hypotension and bradycardia also occur in response to intracerebroventricular administration of N/OFQ 8,52 responses that can be abolished by antagonising the NOP receptor with UFP-101. 6,57 Administration of N/OFQ via microinjection directly into the rostral ventrolateral medulla and paraventricular nucleus (areas of the brain also involved in cardiovascular regulation) also reduces blood pressure and heart rate compared to injection of the same volume of saline. 58 These responses are not seen in NOP knockout animals.…”

“…6 Subsequently, NOP mRNA was found in the thymus, lymph nodes, spleen and splenocytes of pigs 9 and more types of human leucocytes ( Figure 1). mRNA for prepronociceptin (ppN/OFQ), the precursor for nociceptin, was later also found to be expressed on human peripheral blood lymphocytes.…”

“…The ligand is a peptide of 17 amino acids in length and is defined as a non-classical member of the opioid family, since it has a similar sequence to classical opioids but it does not bind to their receptors. 6 N/OFQ has many other roles distinct from its role in the pain pathway (for which it is most well-known), such as roles in depression, anxiety, stroke and heart failure. Leucocytes, cytokines and the N/OFQ system in sepsis.…”

“…Inflammatory responses have significant genetic variability. 6. Extrapolations of data from animal or laboratory models may be limited and translational research is needed.…”

“…5,6 The nociceptin system comprises the nociceptin receptor (NOP) and the ligand that binds to the receptor (N/OFQ). The ligand is a peptide of 17 amino acids in length and is defined as a non-classical member of the opioid family, since it has a similar sequence to classical opioids but it does not bind to their receptors.…”