PHARMACOLOGICAL CHARACTERIZATION OF NOCICEPTIN RECEPTOR - AN IN-VITROSTUDY

The newly discovered neuropeptide nociceptin (NC) (alias orphanin FQ) was tested for its potential direct effects as well as for its ability to modify the electrically evoked contractions in several isolated or gans suspended in vitro. NC was inactive both as stimulant and as inhi bitor of smooth muscle in several preparations, whereas it inhibited t he contractions induced by electrical field stimulation in the mouse v as deferens and guinea pig ileum. NC showed the same potency (IC50 = 1 0 nM) in the two preparations. However, it was significantly more effe ctive in the mouse vas deferens (maximal effect -80%) than in the guin ea pig ileum (maximal effect -50%). The inhibitory effect exerted by N C in the two preparations was not affected by naloxone or more selecti ve opioid receptor antagonists. Moreover, by truncation of C-terminal sequences, NC fragments were designed. These fragments were subsequent ly tested in the mouse vas deferens and in the guinea pig ileum: NC(1- 13)-NH2 was the smallest peptide maintaining the same efficacy and pot ency as the natural peptide. Finally, NC-NH2 and its fragments NC(1-13 )-NH2 and NC(1-9)-NH2 were modified by substituting the phenylalanine 1 residue with a tyrosine. These peptides were tested in the guinea pi g ileum, where they behaved as mixed NC-opioid receptor agonists ([Tyr (1)]NC-NH2 and [Tyr(1)]NC(1-13)-NH2) or as pure opioid receptor agonis ts ([Tyr(1)]NC(1-9)-NH2. In conclusion, the present paper demonstrated that the electrically stimulated mouse vas deferens and guinea pig il eum can be used as a sensitive bioassay for studying the pharmacology of NC and related compounds.