Pharmacological characterization of the nociceptin/orphanin FQ receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol]: in vivo studies.
The excellent pharmacological profile displayed by the selective nociceptin/orphanin FQ (N/OFQ) peptide (NOP) receptor antagonist SB-612111 [(-)-cis-1-methyl-7-[[4-(2,6-dichlorophenyl)piperidin-1-yl]methyl]-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol] in vitro prompted us to investigate the actions of this compound in vivo. In the mouse tail withdrawal assay, SB-612111 given i.p. up to 3 mg/kg did not modify per se tail withdrawal latencies but was able to prevent the pronociceptive and the antinociceptive action of 1 nmol of N/OFQ given i.c.v. and i.t., respectively. In food intake studies performed in sated mice, SB-612111 (1 mg/kg i.p.) had no effect on food consumption but fully prevented the orexigenic effect of 1 nmol of N/OFQ i.c.v. In 17-h food-deprived mice, the opioid receptor antagonist naltrexone (1 mg/kg s.c.), but not SB-612111 (1 and 10 mg/kg i.p.), produced a statistically significant reduction of food intake. In the mouse forced swimming and tail suspension tests, SB-612111 (1-10 mg/kg) reduced immobility time. The antidepressant-like effect elicited by SB-612111 in the forced swimming test was reversed by the i.c.v. injection of 1 nmol of N/OFQ and no longer evident in mice knockout for the NOP receptor gene. In conclusion, the present findings demonstrate that SB-612111 behaves in vivo as a potent and selective NOP antagonist and suggest that the N/OFQ-NOP receptor endogenous system plays an important role in regulating mood-related behaviors. The use of SB-612111 in future pathophysiological studies will certainly contribute to define the therapeutic potential of selective NOP receptor antagonists in different disease areas.
Rizzi
Anna
A
Department of Experimental and Clinical Medicine, Section of Pharmacology, University of Ferrara, Ferrara, Italy.
Gavioli
Elaine C
EC
Marzola
Giuliano
G
Spagnolo
Barbara
B
Zucchini
Silvia
S
Ciccocioppo
Roberto
R
Trapella
Claudio
C
Regoli
Domenico
D
Calò
Girolamo
G
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology; D003508:Cycloheptanes / Q000494:pharmacology*; D004435:Eating / Q000187:drug effects; D019417:Hindlimb Suspension; D008124:Locomotion / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D009292:Narcotic Antagonists / Q000494:pharmacology; D010146:Pain / Q000503:physiopathology / Q000517:prevention & control; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000494:pharmacology*; D011957:Receptors, Opioid / Q000235:genetics / Q000502:physiology; D013550:Swimming; D000094942:Nociceptin Receptor
D000928:Antidepressive Agents; D003508:Cycloheptanes; D009292:Narcotic Antagonists; D010880:Piperidines; D011957:Receptors, Opioid; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; D000094942:Nociceptin Receptor; C000722287:Oprl1 protein, mouse