Central and peripheral role of the nociceptin/orphaninFQ system on normal and disturbed colonic motor function and faecal pellet output in the rat

Abstract

In this study, seeking further information on the role of the nociceptin/orphanin FQ (N/OFQ)-ergic system in normal and disturbed colonic motor function in rats, we compared the colonic effects of UFP-112, a novel highly potent agonist, with those of N/OFQ. When injected intracerebroventricularly (i.c.v.) and intraperitoneally (i.p.), UFP-112 and N/OFQ increased bead expulsion time in a statistically significant and dose-related manner and reduced the percentage of rats with castor oil-induced diarrhoea. UFP-112 showed greater efficacy, higher potency and longer-lasting inhibitory effects than N/OFQ, and pretreatment with UFP-101, a selective antagonist, blocked the N/OFQ analogue-induced responses in both tests. When injected i.c.v., UFP-112 and N/OFQ inhibited corticotrophin releasing factor- and restrain stress-stimulated faecal pellet excretion significantly and in a dose-related manner. Conversely, when injected peripherally both peptides significantly inhibited colonic propulsive motility but did so in a non-dose-related manner. In conclusion, these findings indicate that, in the rat, the central and peripheral N/OFQ systems have an inhibitory role in modulating distal colonic propulsive motility under physiological and pathological conditions. UFP-112 therefore promises to be a useful pharmacological tool for investigating the role of the N/OFQ system in motor functions in the distal colonic tract under physiological and pathological conditions.

Activation of the endogenous nociceptin system by selective nociceptin receptor agonist SCH 221510 produces antitransit and antinociceptive effect: a novel strategy for treatment of diarrhea‐predominant IBS

“…As regards GI transit, in the proximal colon nociceptin induced phasic contractions, while it caused propulsive contractions in the distal colon . Moreover, nociceptin increased gastric acid secretion and delayed gastric emptying after central, but not peripheral injection . Furthermore, peripheral injections of nociceptin may either increase, through reduction in purinergic inhibitory motorneuron activity in myenteric plexus or decrease GI motility.…”

Nociceptin Inhibits Uterine Contractions in Term-Pregnant Rats by Signaling Through Multiple Pathways1

“…Outside the brain, OPRL1 has been detected in the rat peripheral ganglia, airways, and intestines; the mice heart, vas deferens, and colon; the guinea pig retina; and in the human airways and mononuclear cells [6][7][8][9][10][11]. As regards the visceral smooth muscles, PNOC has been found to inhibit nonadrenergic-noncholinergic bronchoconstriction in the guinea pig airways via the prejunctional modulation of tachykinin release [12] and to inhibit distal colon motility in the rat [13]. However, the possible actions of PNOC on the smooth muscle of the female reproductive organs have not been discussed.…”

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

“…Of particular interest, studies conducted in two models of stress‐induced colonic motor dysfunction, the peripheral administration of N/OFQ and of UFP‐112 (a synthetic potent and long‐lasting NOP receptor agonist) reduce fecal pellet output stimulated by restraint stress or by previous injection of CRF, supporting the hypothesis that the endogenous N/OFQergic system works in antagonism to CRF‐induced intestinal transit alterations. These interesting results are in line with the hypothesis supported in other experimental conditions that the N/OFQergic system behaves as a functional antagonist of some central and peripheral effects induced by stress and mediated by the activation of hypothalamic–pituitary–adrenal axis and CRF.…”