Predominance of δ-Opioid-Binding Sites in the Porcine Enteric Nervous System

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Abstract
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.
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