title: Effects of Ro 64-6198 in nociceptin/orphanin FQ-sensitive isolated tissues.
abstract: The pharmacological profile of the non-peptide OP4 receptor (ORL1, LC132) agonist, Ro 64-6198, was investigated, in three electrically stimulated nociceptin/orphanin FQ (NC)-sensitive preparations, namely the mouse and rat vas deferens and the guinea pig ileum. Ro 64-6198 mimicked the inhibitory effect of NC in the three preparations, while showing slow kinetics of action and a slowly reversible effect compared to the fast and immediately and completely reversible effect of the natural peptide. Ro 64-6198 displayed similar pEC50 and Emax values as NC in the mouse and rat vas deferens while it was 100-fold less potent but more efficacious (higher Emax) than NC in the guinea pig ileum. In the rat vas deferens the effects of Ro 64-6198 were antagonised by [Nphe1]NC(1-13)NH2 and J-113397 with pKB values (6.30 and 8.05, respectively) similar to those obtained against NC (6.20 and 7.77, respectively). Naloxone (1 microM) was inactive. In the guinea pig ileum a clear shift of the concentration response curve to Ro 64-6198 was obtained only using a cocktail of antagonists (naloxone + [Nphe1]NC(1-13)NH2 or naloxone + J-113397). In the mouse vas deferens the antagonists were inactive against Ro 64-6198 either when tested alone or in combination. Therefore, Ro 64-6198 behaved as a selective OP4 receptor agonist only in the rat tissue. These results suggest a physiological heterogeneity in OP4 receptors across tissues and species and may explain why, when tested in vivo, Ro 64-6198 mimics the potent anxiolytic effect of NC better in the rat than in the mouse.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Ferrara, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Rizzi
authors.forename: R
authors.initials: R
authors.lastname: Bigoni
authors.forename: A
authors.initials: A
authors.lastname: Rizzi
authors.forename: F
authors.initials: F
authors.lastname: Jenck
authors.forename: J
authors.initials: J
authors.lastname: Wichmann
authors.forename: R
authors.initials: R
authors.lastname: Guerrini
authors.forename: D
authors.initials: D
authors.lastname: Regoli
authors.forename: G
authors.initials: G
authors.lastname: Calo
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D051379:Mice; D018847:Opioid Peptides / Q000494:pharmacology*; D009928:Organ Specificity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011957:Receptors, Opioid / Q000819:agonists / Q000502:physiology; D013045:Species Specificity; D013141:Spiro Compounds / Q000494:pharmacology*; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D014151:Anti-Anxiety Agents; D007093:Imidazoles; D018847:Opioid Peptides; D011957:Receptors, Opioid; D013141:Spiro Compounds; D014665:Vasodilator Agents; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C408068:Ro 64-6198