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 language | English |
|---|---|
| Pages (from-to) | 450-456 |
| Number of pages | 7 |
| Journal | Naunyn-Schmiedeberg's Archives of Pharmacology |
| Volume | 365 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2002 |
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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 journal › Article
}
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
UR - http://www.scopus.com/inward/record.url?scp=0035987107&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035987107&partnerID=8YFLogxK
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 -