[Nphe(1)]nociceptin-(1-13)NH(2) selectively antagonizes nociceptin effects in the rabbit isolated ileum.

When suspended in vitro in isolated organ baths, segments of the rabbit ileum show a fairly strong and stable spontaneous activity, which derives from the continuous release of acetylcholine and the activation of muscarinic receptors, since the activity is completely eliminated by atropine. Dynorphin A (pEC(50): 8.6+/-0.07), neuropeptide Y and its congener human pancreatic polypeptide (pEC(50): 9.40+/-0.10), and nociceptin (pEC(50): 8.08+/-0.12) dose-dependently inhibit the spontaneous activity through the activation of receptors, which are specifically antagonised respectively by naloxone (pA(2): 7.17+/-0.12), 2-(naphtalen-1-ylamino)-3-phenylpropionitrile (JCF 104; pA(2): 5. 80+/-0.10), and [Nphe(1)]nociceptin-(1-13)NH(2) (pA(2): 6.17+/-0.19). This last compound, a selective nociceptin-receptor (OP(4)) antagonist, inhibits the effect of nociceptin in a competitive manner, as demonstrated by Schild analysis. [Nphe(1)]nociceptin-(1-13)NH(2) also antagonizes the effects of other OP(4) receptor ligands such as the full agonist, nociceptin-(1-13)-NH(2), and the partial agonists, [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin-(1-13)-NH(2) (intrinsic activity (alpha(E))=0.5) and Ac-RYYWK-NH(2) (alpha(E)=0.5), with pA(2) values ranged from 5.8 to 6.2. These results indicate that the functional site mediating the inhibitory effect of nociceptin in the rabbit ileum, is pharmacologically identical to the OP(4) sites of other species (mouse, rat, guinea pig, man), since the potencies (pA(2) values) of the pure and competitive antagonist [Nphe(1)]nociceptin-(1-13)NH(2) is very similar to the values obtained in the other species. Moreover, the rabbit ileum is one of the few isolated organs that allow classifying compounds, which interact with OP(4) receptors as full agonists, partial agonists, or pure antagonists.