Pharmacological characterisation of [(pX)Phe4]nociceptin(1-13)NH2 analogues. 2. In vivo studies.
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.
Rizzi
Anna
A
Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, University of Ferrara, Via Fossato di Mortara 17-19, 44100 Ferrara, Italy.
Salis
Maria Bonaria
MB
Ciccocioppo
Roberto
R
Marzola
Giuliano
G
Bigoni
Raffaella
R
Guerrini
Remo
R
Massi
Maurizio
M
Madeddu
Paolo
P
Salvadori
Severo
S
Regoli
Domenico
D
Calo'
Girolamo
G
D000818:Animals; D004435:Eating / Q000187:drug effects / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018847:Opioid Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D010446:Peptide Fragments / Q000737:chemistry* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011957:Receptors, Opioid / Q000502:physiology; D013329:Structure-Activity Relationship; D000094942:Nociceptin Receptor
D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; C439964:nociceptin (1-13) amide; D000094942:Nociceptin Receptor