The endogenous nociceptin/orphanin FQ‐NOP receptor system as a potential therapeutic target for intestinal disorders

Abstract

In 1995, by reverse pharmacology approach, used here for the first time in the history of pharmacology, nociceptin/orphanin FQ (N/OFQ) has been discovered as the endogenous ligand of a preidentified receptor named opioid receptor like 1. Subsequent studies showed that N/OFQ and its receptor (N/OFQergic system) are widely distributed in central and peripheral nervous systems as well as in peripheral organs of human and animals, and represent a system that is involved in a very large range of biological functions such as pain perception, intestinal motility and secretion, immune modulation, stress. From the time of its discovery to now, a high number of NOP agonists and antagonists have been synthesized and tested in various pathologies. Nevertheless, none of the molecules targeting N/OFQergic system have currently succeeded in going through clinical trials concerning gut pathologies, indicating that further studies are required. The work from Dr. Fichna et al., published in the present issue of Neurogastroenterology and Motility, adds another brick in the wall of understanding the role of N/OFQergic system in IBS-D pathology by the pharmacological evaluation of a new NOP receptor agonist, SCH 221510, in animal models of intestinal alterations (diarrhea and visceral hyperalgesia). Interestingly, authors report clinical data confirming the involvement of N/OFQergic system in IBS-D patients and, consequently, suggest this system as a valuable therapeutic target for IBS-D pathology. This minireview aims to give a brief summary of experimental and clinical studies focusing on the N/OFQergic system as pharmacological target for the therapeutic treatment of intestinal pathologies such as IBS and IBD.

Nociceptin Opioid Receptor (NOP) as a Therapeutic Target: Progress in Translation from Preclinical Research to Clinical Utility

“…Interestingly, only the ip and oral routes of administration were effective for the antinociceptive effects of 12 ; direct intracolonic administration did not have an effect on the intestinal swelling observed in these animals . It has been speculated that N/OFQ and therefore NOP agonists may play a role in neurogenic inflammation and pain, such as that in IBD . These interesting findings, however, warrant further investigation before these applications can be translated to the clinic.…”

“…114 It has been speculated that N/OFQ and therefore NOP agonists may play a role in neurogenic inflammation and pain, such as that in IBD. 115 These interesting findings, however, warrant further investigation before these applications can be translated to the clinic. SCH486757 (4), 116 a NOP agonist, also belongs to the Nbenzhydrylnortropane series of NOP ligands developed by Schering-Plough (Figure 1).…”

“…114 It has been speculated that N/OFQ and therefore NOP agonists may play a role in neurogenic inflammation and pain, such as that in IBD. 115 These interesting findings, however, warrant further investigation before these applications can be translated to the clinic.…”

Parsing the hedonic and motivational influences of nociceptin on feeding using licking microstructure analysis in mice

“…For example, NOC is found in the gastrointestinal tract, where it contributes to bowel homeostasis by affecting secretion and motility (Agostini and Petrella, 2014; Sobczak et al, 2013). Gut alterations resulting from NOP deletion may indeed lead to intestinal pathologies that suppress feeding behavior, including voluntary drinking of sweet solutions.…”

A Healthy Gut for a Healthy Brain: Preclinical, Clinical and Regulatory Aspects

“…Nerve endings can also release peptidergic neurotransmitters ( e.g. , calcitonin gene-related peptide; somatostatin, substance P, vasoactive intestinal peptide, nociceptin, pancreatic polypeptide, gastrin, cholecystokinin, neurotensin and bombesin), or gas as nitric oxide [ 6 - 14 ]. The interaction of these neurotransmitters with their specific receptors generates excitatory or inhibitory responses.…”