Effects of Ro 64-6198 it nociceptin/orphanin FQ-sensitive isolated tissues

The pharmacological profile of the non-peptide OP4 receptor (ORL1, LC132) a gonist, Bo 64-6198, was investigated, in three electrically stimulated noci ceptin/orphanin FQ (NC)-sensitive preparations, namely the mouse and rat va s deferens and the guinea pig ileum. Ro 64-6193 mimicked the inhibitory eff ect of NC in the three preparations, while showing slow kinetics of action and a slowly reversible effect compared to the fast and immediately and com pletely reversible effect of the natural peptide. Ro 64-6198 displayed simi lar pEC(50) and E-max values as NC in the mouse and rat vas deferens while it was 100-fold less potent but more efficacious (higher E-max) than NC in the guinea pig ileum. In the rat vas deferens the effects of Ro 64-6198 wer e antagonised by [Nphe(1)]NC(1-13)NH2 and J-113397 with pK(B) values (6.30 and 8.05, respectively) similar to those obtained against NC (6.20 and 7.77 , respectively). Naloxone (1 muM) was inactive. In the guinea pig ileum a c lear shift of the concentration response curve to Ro 64-6198 was obtained o nly using a cocktail of antagonists (naloxone + [Nphe(1)]NC(1-13)NH2 or nal oxone + J-113397). In the mouse vas deferens the antagonists were inactive against Ro 64-6198 either when tested alone or in combination. Therefore, R o 64-6198 behaved as a selective OP4 receptor agonist only in the rat tissu e. These results suggest a physiological heterogeneity in OP4 receptors acr oss tissues and species and may explain why, when tested in vivo, Re 64-619 8 mimics the potent anxiolytic effect of NC better in the rat than in the m ouse.