title: Functional antagonism between nociceptin/orphanin FQ and corticotropin-releasing factor in rat anxiety-related behaviors: involvement of the serotonergic system.
abstract: Nociceptin/orphanin FQ (N/OFQ) acts as an anxiolytic-like agent in the rat and behaves as a functional antagonist of corticotropin-releasing factor (CRF) due to its ability to oppose CRF biological actions. In response to stress, CRF triggers changes in neurotransmitter systems including serotonin (5-HT). The role of 5-HT1A receptor in anxiety has been supported by preclinical and clinical studies. The present study investigated the possible functional antagonism between N/OFQ (1nmol/rat) and CRF (0.2nmol/rat) in anxiety-related conditions in rats, using elevated plus maze and defensive burying tests, in order to confirm previous literature results. Moreover, possible changes in the serotonergic system were studied in areas rich of serotonergic neurons: frontal cortex and pons. In both tests N/OFQ showed anxiolytic-like effects while CRF displayed anxiogenic-like effects. N/OFQ before CRF treatment counteracted the anxiogenic-like effects evoked by CRF. In frontal cortex, N/OFQ significantly decreased 5-HT levels but did not modify the hydroxyindoleacetic acid (5-HIAA) ones; CRF modified neither 5-HT nor 5-HIAA content but counteracted changes induced by N/OFQ alone. In pons, N/OFQ induced no change in serotonergic activity while CRF significantly decreased 5-HT levels and increased 5-HIAA content. The two peptides' combination reinstated serotonergic parameters to controls. In frontal cortex, N/OFQ increased the 5HT1A receptor density but reduced its affinity, while CRF alone did not induce any change. In pons, CRF decreased 5HT1ABmax and KD whereas N/OFQ was ineffective. All biochemical modifications were reverted by N/OFQ plus CRF treatment. The present study confirms that N/OFQ counteracts CRF anxiogenic-like effects in the behavioral tests evaluated. These effects may involve central serotonergic mechanisms since N/OFQ plus CRF induces a reversion of serotonergic changes provoked by single peptide. Our data support the hypothesis that N/OFQ may behave as functional CRF antagonist, this action being of interest for the treatment of anxiety disorders.
authors.affiliation: Department of Biomedical, Metabolic Sciences and Neurosciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Filaferro
authors.affiliation: Department of Life Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Ruggieri
authors.affiliation: Department of Life Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Novi
authors.affiliation: Department of Medical Sciences, Section of Pharmacology, and National Institute of Neuroscience, University of Ferrara, Via Fossato di Mortara 19, 44121 Ferrara, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Calò
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Macerata, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Cifani
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Via Madonna delle Carceri 9, 62032 Camerino, Macerata, Italy.
authors.forename: M V
authors.initials: MV
authors.lastname: Micioni Di Bonaventura
authors.affiliation: Department of Biomedical, Metabolic Sciences and Neurosciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Sandrini
authors.affiliation: Department of Life Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Via G. Campi 287, 41125 Modena, Italy. Electronic address: giovanni.vitale@unimore.it.
authors.forename: G
authors.initials: G
authors.lastname: Vitale
mesh_terms: D000818:Animals; D001007:Anxiety / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D018847:Opioid Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D012701:Serotonin / Q000502:physiology*; D000097629:Nociceptin
chemical_list: D003346:Corticotropin-Releasing Hormone; D006897:Hydroxyindoleacetic Acid; D018847:Opioid Peptides; D044282:Receptor, Serotonin, 5-HT1A; D012701:Serotonin; D000097629:Nociceptin
keywords: Anxiety; Corticotropin-releasing factor (CRF); Functional antagonism; Nociceptin/orphanin FQ (N/OFQ); Serotonergic system