PT - JOURNAL ARTICLE AU - Daniela Rizzi AU - Anna Rizzi AU - Raffaella Bigoni AU - Valeria Camarda AU - Giuliano Marzola AU - Remo Guerrini AU - Carmela De Risi AU - Domenico Regoli AU - Girolamo Calo' TI - [Arg<sup>14</sup>,Lys<sup>15</sup>]Nociceptin, a Highly Potent Agonist of the Nociceptin/Orphanin FQ Receptor: in Vitro and in Vivo Studies AID - 10.1124/jpet.300.1.57 DP - 2002 Jan 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 57--63 VI - 300 IP - 1 4099 - http://jpet.aspetjournals.org/content/300/1/57.short 4100 - http://jpet.aspetjournals.org/content/300/1/57.full SO - J Pharmacol Exp Ther2002 Jan 01; 300 AB - The nociceptin (NC)/orphanin FQ analog, [Arg14,Lys15]NC, has been recently demonstrated to behave as a potent agonist at the human recombinant NC receptors (OP4). In this study, we evaluated the pharmacological profile of [Arg14,Lys15]NC in vitro on the native OP4 receptors expressed in isolated tissues and in vivo in the locomotor activity and the tail-withdrawal assays in mice. On isolated tissues, [Arg14,Lys15]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 [Arg14,Lys15]NC were not modified by 1 μM naloxone, although antagonized by the OP4 receptor antagonists [Nphe1]NC(1–13)NH2(pA 2 ≅ 6) and (±)trans-1-[1-cyclooctylmethyl-3hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) (pA 2 ≅ 8). In the rat vas deferens, a cocktail of peptidase inhibitors increased the maximal effects of NC, its analog, and the pEC50 of NC (by 4-fold); the potency of [Arg14,Lys15]NC was not significantly modified by peptidase inhibitors. In in vivo experiments, [Arg14,Lys15]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, [Arg14,Lys15]NC was about 30-fold more potent than NC and produced longer lasting effects. Taken together, the present data demonstrate that [Arg14,Lys15]NC behaves as a highly potent agonist of the OP4 receptor and is able to produce long-lasting effects in vivo, compared with the natural ligand NC. NCnociceptinJ-113397(±)trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-2H-benzimidazol-2-oneANOVAanalysis of variance