[Arg(14), Lys(15)]nociceptin, a highly potent agonist of the nociceptin/orphanin FQ receptor: in vitro and in vivo studies

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 (pA2 ≅ 6) and (±)trans-1-[1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3- ethyl-1,3-dihydro-2H-benzimidazol-2-one (J-113397) (pA2 ≅ 8). In the rat vas deferens, a cocktail of peptidase inhibitors increased ...