Protective and worsening peripheral nociceptin/orphanin FQ receptor-mediated effect in a rat model of experimental colitis.
Nociceptin/orphanin FQ (N/OFQ) and nociceptin orphanin peptide (NOP) receptors represent an endogenous system modulating gastrointestinal functions and inflammation. We investigated the peripheral effect of N/OFQ and of UFP-101, the NOP antagonist, in a model of colitis induced by TNBS (2,4,6 trinitrobenzenesulphonic acid; 60mg/kg). Male rats received two intraperitoneal injections per day of N/OFQ, UFP-101 or saline for 3 days after colitis induction. Four days after TNBS, animals were sacrificed and colonic histological damage, myeloperoxidase (MPO) activity and cytokine (IL-1β and IL-10) levels were evaluated. N/OFQ plasmatic levels were assessed by radioimmunoassay. TNBS increased all the inflammatory variables considered. In colitic rats, N/OFQ (0.02 and 0.2nmol/kg) improved microscopic damage, MPO activity and decreased IL-1β levels in comparison with TNBS group, whereas at the highest dose (20nmol/kg) the peptide worsened colitis. UFP-101 at the dose of 1nmol/kg, without pharmacological activity, antagonised the protective effect of N/OFQ (0.2nmol/kg) on colitis, but at a dose level of 3 and 10nmol/kg worsened inflammation, revealing the endogenous N/OFQergic system protective role. N/OFQ plasmatic levels were not modified in TNBS-treated rats compared with controls, whereas they were reduced in rats treated with the doses of UFP-101 aggravating colitis. In conclusion, peripheral low doses of N/OFQ have a beneficial effect on colonic inflammation in rats. In contrast, N/OFQ at a dose 100-1000-fold higher than those that protect worsens colitis, probably through different mechanisms. The peripheral N/OFQergic system can represent a new field of investigation in some intestinal inflammatory conditions.
Department of Physiology and Pharmacology V. Erspamer, Sapienza University of Rome, Rome, Italy. carla.petrella@uniroma1.it
Carla
C
Petrella
Chiara
C
Giuli
Maria
M
Broccardo
Helene
H
Eutamene
Christel
C
Cartier
Mathilde
M
Leveque
Andrea
A
Bedini
Santi
S
Spampinato
Lionel
L
Bueno
Vassilia
V
Theodorou
Giovanna
G
Improta
Simona
S
Agostini
D000818:Animals; D003092:Colitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007413:Intestinal Mucosa / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D018847:Opioid Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000378:metabolism*; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology; D000094942:Nociceptin Receptor; D000097629:Nociceptin
D016207:Cytokines; D018847:Opioid Peptides; D011957:Receptors, Opioid; D014302:Trinitrobenzenesulfonic Acid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C000722285:Oprl1 protein, rat