Effect of agonist (Nociceptin/Orphanin FQ) and antagonist (UFP-101) of the NOP receptor system in a rat model of experimental colitis

Nociceptin/OrphaninFQ (N/OFQ) and Nociceptin Orphan Peptide (NOP) receptors represent an endogenous system modulating gastrointestinal functions and inflammation. We investigated the effect of the peripheral administration of the agonist N/OFQ (0.02-0.2-2-20 nmol/kg) and the antagonist UFP-101 (1-3-10 nmol/kg) on some inflammatory variables in a rat model of colitis induced by intracolonic (IC) instillation of TNBS (2,4,6 trinitrobenzensulfonic acid) (60 mg/kg, IC). Male Wistar rats received two intraperitoneal (IP) injections per day of N/OFQ, or UFP-101, or saline for three days after induction of colitis. Four days after TNBS, animals were sacrificed and colonic histological damage, myeloperoxidase (MPO) activity, cytokine (IL-1 and IL-10) levels were evaluated. N/OFQ plasmatic concentration was assessed by radioimmunoassay. TNBS increased all the inflammatory variables considered. In colitic rats, N/OFQ, at 0.02 and 0.2nmol/kg, improved microscopic damage and MPO activity, and decreased IL-1 levelsin comparison with TNBS group, whereas at the highest dose (20 nmol/kg) worsened colitis. UFP-101, which at dose of 3 and 10 nmol/kg increased inflammation, at a dose of 1 nmol/kg, without intrinsic activity, antagonized the protective effect of N/OFQ (0.2 nmol/kg) on colitis. N/OFQ plasmatic levels, which were not modified in TNBS-treated rats compared with controls, decreased in rats treated with UFP-101 at the doses (3 and 10 nmol/kg) that worsen colitis. In conclusion: 1) peripheral low doses of N/OFQ have immunosuppressive and anti-inflammatory effects on TNBS colitis in rats; 2) N/OFQ, at a dose 1000-10000 fold higher than those that protect, worsens colitis. 3) The endogenous peripheral N/OFQergic system plays a protective role in this experimental pathological condition.