title: [Arg(14),Lys(15)]nociceptin, a highly potent agonist of the nociceptin/orphanin FQ receptor: in vitro and in vivo studies.
abstract: The nociceptin (NC)/orphanin FQ analog, [Arg(14),Lys(15)]NC, has been recently demonstrated to behave as a potent agonist at the human recombinant NC receptors (OP(4)). In this study, we evaluated the pharmacological profile of [Arg(14),Lys(15)]NC in vitro on the native OP(4) receptors expressed in isolated tissues and in vivo in the locomotor activity and the tail-withdrawal assays in mice. On isolated tissues, [Arg(14),Lys(15)]NC mimicked the effects of NC, showing similar maximal effects but higher potencies (17-fold in the mouse vas deferens, 10-fold in the rat vas deferens, and about 5-fold in the guinea pig ileum and mouse colon). In these preparations, the effects of [Arg(14),Lys(15)]NC were not modified by 1 microM naloxone, although antagonized by the OP(4) receptor antagonists [Nphe(1)]NC(1-13)NH(2) (pA(2) congruent with 6) and (+/-)trans-1-[1-cyclooctylmethyl-3hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) (pA(2) congruent with 8). In the rat vas deferens, a cocktail of peptidase inhibitors increased the maximal effects of NC, its analog, and the pEC(50) of NC (by 4-fold); the potency of [Arg(14),Lys(15)]NC was not significantly modified by peptidase inhibitors. In in vivo experiments, [Arg(14),Lys(15)]NC mimicked the effects of NC, producing, after intracerebroventricular administration, pronociceptive effects in the tail-withdrawal assay and inhibiting the locomotor activity of the mice. In both assays, [Arg(14),Lys(15)]NC was about 30-fold more potent than NC and produced longer lasting effects. Taken together, the present data demonstrate that [Arg(14),Lys(15)]NC behaves as a highly potent agonist of the OP(4) receptor and is able to produce long-lasting effects in vivo, compared with the natural ligand NC.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Rizzi
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.forename: Raffaella
authors.initials: R
authors.lastname: Bigoni
authors.forename: Valeria
authors.initials: V
authors.lastname: Camarda
authors.forename: Giuliano
authors.initials: G
authors.lastname: Marzola
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Carmela
authors.initials: C
authors.lastname: De Risi
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000008:administration & dosage / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists; D013045:Species Specificity; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D001562:Benzimidazoles; D009270:Naloxone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C402921:J 113397; C444644:nociceptin, Arg(14)-Lys(15)-