TY - JOUR
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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U2 - 10.1007/s00210-002-0549-7
DO - 10.1007/s00210-002-0549-7
M3 - Article
C2 - 12070758
AN - SCOPUS:0035987107
VL - 365
SP - 450
EP - 456
JO - Naunyn-Schmiedeberg's Archives of Pharmacology
JF - Naunyn-Schmiedeberg's Archives of Pharmacology
SN - 0028-1298
IS - 6
ER -