Pharmacological characterisation of [(px)phe 4]nociceptin(1-13)nh 2 analogues: 2. In vivo studies

Anna Rizzi, Maria Salis, Roberto Ciccocioppo, Giuliano Marzola, Raffaella Bigoni, Remo Guerrini, Maurizio Massi, Paolo Madeddu, Severo Salvadori, Domenico Regoli, Girolamo Calo

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Abstract

As part of a structure-activity study focused on the Phe 4 residue of nociceptin (NC) (1-13)NH 2, we identified two highly potent and selective agonists for the OP 4 receptor, [(pF)Phe 4]NC(1-13)NH 2 and [(pNO 2)Phe 4]NC(1-13)NH 2, whose in vitro pharmacological profiles have been described in the companion paper. In the present study, we investigated the actions of [(pF)Phe 4]NC(1-13)NH 2 and compared it with those of NC(1-13)NH 2 in a battery of vivo assays. In the locomotor activity test in mice, 1 nmol NC(1-13)NH 2 given intracerebroventricularly (i.c.v.) caused a significant decrease (about 70% inhibition) in activity for the first 15 min following injection; [(pF)Phe 4]NC(1-13)NH 2, 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 OP 4 receptor antagonist [Nphe 1]NC(1-13)NH 2 (10 nmol, i.c.v.). In the tail-withdrawal assay in mice, [(pF)Phe 4]NC(1-13)NH 2 mimicked the effects of NC(1-13)NH 2 producing pronociceptive and antimorphine effects following i.c.v. administration. In both experimental paradigms, the actions of [(pF)Phe 4]NC(1-13)NH 2 were longer lasting (>60 min) compared to those of NC(1-13)NH 2 (ca. 30 min). In unanaesthetised normotensive mice, bolus intravenous (i.v.) injection of 100 nmol/kg of [(pF)Phe 4]NC(1-13)NH 2 decreased mean blood pressure and heart rate; these effects were longer lasting than those elicited by the same dose of NC(1-13)NH 2. I.c.v. administration of [(pF)Phe 4]NC(1-13)NH 2 dose-dependently stimulated feeding in rats, and was about tenfold more potent than NC(1-13)NH 2. Collectively, the present data demonstrate that, in a variety of in vivo assays, NC(1-13)NH 2 and [(pF)Phe 4]NC(1-13)NH 2 mimicked the actions of NC. [(pF)Phe 4]NC(1-13)NH 2 was more potent and its in vivo effects were longer lasting than those of NC(1-13)NH 2 and NC.

Original languageEnglish
Pages (from-to)450-456
Number of pages7
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume365
Issue number6
DOIs
Publication statusPublished - 2002

Keywords

  • [(pF)Phe ]NC(1-13)NH
  • Mouse blood pressure
  • Mouse heart rate
  • Mouse locomotor activity
  • Mouse tail withdrawal
  • Nociceptin/orphanin FQ
  • OP receptor
  • Rat food intake

ASJC Scopus subject areas

  • Pharmacology

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    Rizzi, A., Salis, M., Ciccocioppo, R., Marzola, G., Bigoni, R., Guerrini, R., Massi, M., Madeddu, P., Salvadori, S., Regoli, D., & Calo, G. (2002). Pharmacological characterisation of [(px)phe 4]nociceptin(1-13)nh 2 analogues: 2. In vivo studies. Naunyn-Schmiedeberg's Archives of Pharmacology, 365(6), 450-456. https://doi.org/10.1007/s00210-002-0549-7