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

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Pharmacology
nociceptin
Locomotion
Intravenous Injections
Tail

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

Cite this

Pharmacological characterisation of [(px)phe 4]nociceptin(1-13)nh 2 analogues : 2. In vivo studies. / Rizzi, Anna; Salis, Maria; Ciccocioppo, Roberto; Marzola, Giuliano; Bigoni, Raffaella; Guerrini, Remo; Massi, Maurizio; Madeddu, Paolo; Salvadori, Severo; Regoli, Domenico; Calo, Girolamo.

In: Naunyn-Schmiedeberg's Archives of Pharmacology, Vol. 365, No. 6, 2002, p. 450-456.

Research output: Contribution to journalArticle

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, vol. 365, no. 6, pp. 450-456. https://doi.org/10.1007/s00210-002-0549-7
Rizzi, Anna ; Salis, Maria ; Ciccocioppo, Roberto ; Marzola, Giuliano ; Bigoni, Raffaella ; Guerrini, Remo ; Massi, Maurizio ; Madeddu, Paolo ; Salvadori, Severo ; Regoli, Domenico ; Calo, Girolamo. / Pharmacological characterisation of [(px)phe 4]nociceptin(1-13)nh 2 analogues : 2. In vivo studies. In: Naunyn-Schmiedeberg's Archives of Pharmacology. 2002 ; Vol. 365, No. 6. pp. 450-456.
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T1 - Pharmacological characterisation of [(px)phe 4]nociceptin(1-13)nh 2 analogues

T2 - 2. In vivo studies

AU - Rizzi, Anna

AU - Salis, Maria

AU - Ciccocioppo, Roberto

AU - Marzola, Giuliano

AU - Bigoni, Raffaella

AU - Guerrini, Remo

AU - Massi, Maurizio

AU - Madeddu, Paolo

AU - Salvadori, Severo

AU - Regoli, Domenico

AU - Calo, Girolamo

PY - 2002

Y1 - 2002

N2 - 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.

AB - 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.

KW - [(pF)Phe ]NC(1-13)NH

KW - Mouse blood pressure

KW - Mouse heart rate

KW - Mouse locomotor activity

KW - Mouse tail withdrawal

KW - Nociceptin/orphanin FQ

KW - OP receptor

KW - Rat food intake

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