Pharmacological characterisation of [(pX)Phe⁴]nociceptin(1-13)NH₂ analogues

Abstract.

As part of a structure–activity study focused on the Phe⁴ residue of nociceptin (NC) (1-13)NH₂, we identified two highly potent and selective agonists for the OP₄ receptor, [(pF)Phe⁴]NC(1-13)NH₂ and [(pNO₂)Phe⁴]NC(1-13)NH₂, whose in vitro pharmacological profiles have been described in the companion paper. In the present study, we investigated the actions of [(pF)Phe⁴]NC(1-13)NH₂ and compared it with those of NC(1-13)NH₂ in a battery of vivo assays.

In the locomotor activity test in mice, 1 nmol NC(1-13)NH₂ given intracerebroventricularly (i.c.v.) caused a significant decrease (about 70% inhibition) in activity for the first 15 min following injection; [(pF)Phe⁴]NC(1-13)NH₂, at the same dose, exerted a similar inhibitory effect that continued until the end of the observation period (30 min). This effect was prevented by the selective OP₄ receptor antagonist [Nphe¹]NC(1-13)NH₂ (10 nmol, i.c.v.). In the tail-withdrawal assay in mice, [(pF)Phe⁴]NC(1-13)NH₂ mimicked the effects of NC(1-13)NH₂ producing pronociceptive and antimorphine effects following i.c.v. administration. In both experimental paradigms, the actions of [(pF)Phe⁴]NC(1-13)NH₂ were longer lasting (>60 min) compared to those of NC(1-13)NH₂ (ca. 30 min). In unanaesthetised normotensive mice, bolus intravenous (i.v.) injection of 100 nmol/kg of [(pF)Phe⁴]NC(1-13)NH₂ decreased mean blood pressure and heart rate; these effects were longer lasting than those elicited by the same dose of NC(1-13)NH₂. I.c.v. administration of [(pF)Phe⁴]NC(1-13)NH₂ dose-dependently stimulated feeding in rats, and was about tenfold more potent than NC(1-13)NH₂.

Collectively, the present data demonstrate that, in a variety of in vivo assays, NC(1-13)NH₂ and [(pF)Phe⁴]NC(1-13)NH₂ mimicked the actions of NC. [(pF)Phe⁴]NC(1-13)NH₂ was more potent and its in vivo effects were longer lasting than those of NC(1-13)NH₂ and NC.