The effects of [Arg 14, Lys 15] nociceptin/orphanin FQ, a highly potent agonist of the NOP receptor, on in vitro and in vivo gastrointestinal functions

• Published in: Peptides (New York, N.Y. : 1980) N.Y. : 1980), 2005-09, Vol.26 (9), p.1590-1597
• Main Authors: Broccardo, M., Linari, G., Guerrini, R., Agostini, S., Petrella, C., Improta, G.
• Format: Article
• Language: English
• Subjects: [Arg 14, Lys 15] N/OFQ; Amylases - metabolism; Animals; Digestive System - drug effects; Dose-Response Relationship, Drug; Gastric Acid - metabolism; Gastric Emptying - drug effects; Gastric Mucosa - drug effects; Gastric Mucosa - metabolism; Gastrointestinal motor and secretory functions; Gastrointestinal Transit - drug effects; Guinea Pigs; In Vitro Techniques; Ligation; Male; Naloxone - pharmacology; Narcotic Antagonists; Nociceptin; Nociceptin Receptor; Opioid Peptides - pharmacology; Pancreas, Exocrine - drug effects; Pancreas, Exocrine - metabolism; Potassium Chloride - pharmacology; Pylorus - surgery; Rats; Rats, Wistar; Receptors, Opioid - agonists; Vasodilator Agents - pharmacology
• ISSN: 0196-9781; 1873-5169
• DOI: 10.1016/j.peptides.2005.02.018

Nociceptin/orphanin FQ (N/OFQ) administered into the lateral left cerebral ventricle of rats has been reported to inhibit in vivo gut motor and secretory functions. Recently, a novel N/OFQ analog, [Arg 14, Lys 15] N/OFQ, was synthesized and demonstrated to behave as a highly potent agonist at the human recombinant N/OFQ peptide (NOP) receptors and to produce long-lasting effects in vivo in mice compared with the natural ligand N/OFQ. In the present study, the pharmacological profile of [Arg 14, Lys 15] N/OFQ was further evaluated and compared with that of N/OFQ in vitro on guinea pig exocrine pancreas and in vivo on gastric emptying, colonic propulsion and gastric acid secretion in rats. [Arg 14, Lys 15] N/OFQ and N/OFQ significantly decreased the KCl-evoked amylase secretion from isolated pancreatic lobules of the guinea pig. In in vivo experiments, [Arg 14, Lys 15] N/OFQ mimicked the effects of N/OFQ, inducing, after intracerebroventricular injection, a delay (up to 70%) in the gastric emptying of a phenol red meal, an increase (about 40 times) of the mean bead colonic expulsion time and a decrease (up to 90%) of gastric acid secretion in water loaded rats after 90 min pylorus ligature. In all these assays, [Arg 14, Lys 15] N/OFQ was more effective than N/OFQ, and its effective doses were at least 10-fold lower than N/OFQ effective doses. The highly selective NOP receptor antagonist, UFP-101, decreased the efficacy of [Arg 14, Lys 15] N/OFQ in in vitro and in vivo assays above reported. These findings: (a) show that pancreatic NOP receptors mediate an in vitro inhibitory effect on stimulated guinea pig amylase secretion; (b) confirm that the stimulation of central NOP receptors exerts an inhibitory control on gastric emptying, colonic motility and gastric secretion in rats and (c) put in evidence that [Arg 14, Lys 15] N/OFQ, being more potent and effective than the natural ligand N/OFQ, represents a new pharmacological tool for the study of the physiological and pharmacological roles mediated by the N/OFQ–NOP receptor system.