title: Effect of novel nociceptin/orphanin FQ-NOP receptor ligands on ethanol drinking in alcohol-preferring msP rats.
abstract: Activation of the NOP receptor by the endogenous ligand nociceptin/orphanin FQ (N/OFQ) reduces alcohol consumption in genetically selected alcohol-preferring Marchigian Sardinian (msP) rats. The present study evaluated the effect of three newly synthesized peptidergic and one brain-penetrating heterocyclic NOP receptor agonists on alcohol drinking in the two bottle choice paradigm. MsP rats were intracerebroventricularly (ICV) injected with the NOP receptor agonists OS-462 (0.5 and 1.0 microg), UFP-102 (0.25 and 1.0 microg) or UFP-112 (0.01 and 0.05 microg), or with Ro 64-6198 (0.3 and 1.0 mg/kg) given intraperitoneally (i.p.) and tested for 10% alcohol consumption. Results showed decreased alcohol consumption after treatment with all three peptidergic NOP receptor agonists (OS-462, UFP-102 and UFP-112). OS-462 (at the 1.0 microg dose) and UFP-102 (at the 0.25 microg dose) induced a significant increase in food intake as well. Surprisingly, Ro 64-6198 was ineffective at the 0.3 mg/kg dose, whereas it increased ethanol and food consumption at the 1.0 mg/kg dose. Pre-treatment with the selective mu-receptor antagonist naloxone (0.5 mg/kg, i.p.) reduced these effects of 1.0 mg/kg of Ro 64-6198. These findings confirm that activation of brain NOP receptors reduces alcohol drinking in msP rats and demonstrate that OS-462, UFP-102 and UFP-112 act as potent NOP receptor agonists. On the other hand, Ro 64-6198 increased alcohol drinking, an effect probably induced by a residual agonist activity of this compound at mu-opioid receptors. Overall, the results indicate that OS-462, UFP-102 and UFP-112 may represent valuable pharmacological tools to investigate the functional role of the brain N/OFQ system.
authors.affiliation: Department of Experimental Medicine and Public Health, University of Camerino, Via Scalzino 3, 62032 Camerino, MC, Italy. daina.economidou@unicam.it
authors.forename: D
authors.initials: D
authors.lastname: Economidou
authors.forename: A
authors.initials: A
authors.lastname: Fedeli
authors.forename: R Martin
authors.initials: RM
authors.lastname: Fardon
authors.forename: F
authors.initials: F
authors.lastname: Weiss
authors.forename: M
authors.initials: M
authors.lastname: Massi
authors.forename: R
authors.initials: R
authors.lastname: Ciccocioppo
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy*; D000818:Animals; D007093:Imidazoles / Q000494:pharmacology*; D008024:Ligands; D008297:Male; D018847:Opioid Peptides / Q000819:agonists* / Q000494:pharmacology*; D051381:Rats; D013141:Spiro Compounds / Q000494:pharmacology*; D000097629:Nociceptin
chemical_list: D007093:Imidazoles; D008024:Ligands; D018847:Opioid Peptides; D013141:Spiro Compounds; D000097629:Nociceptin; C408068:Ro 64-6198; C498512:UFP-102