title: Restraint stress alters nociceptin/orphanin FQ and CRF systems in the rat central amygdala: significance for anxiety-like behaviors.
abstract: Corticotropin releasing factor (CRF) is the primary mediator of stress responses, and nociceptin/orphanin FQ (N/OFQ) plays an important role in the modulation of these stress responses. Thus, in this multidisciplinary study, we explored the relationship between the N/OFQ and the CRF systems in response to stress. Using in situ hybridization (ISH), we assessed the effect of body restraint stress on the gene expression of CRF and N/OFQ-related genes in various subdivisions of the amygdala, a critical brain structure involved in the modulation of stress response and anxiety-like behaviors. We found a selective upregulation of the NOP and downregulation of the CRF1 receptor transcripts in the CeA and in the BLA after body restraint. Thus, we performed intracellular electrophysiological recordings of GABAA-mediated IPSPs in the central nucleus of the amygdala (CeA) to explore functional interactions between CRF and N/OFQ systems in this brain region. Acute application of CRF significantly increased IPSPs in the CeA, and this enhancement was blocked by N/OFQ. Importantly, in stress-restraint rats, baseline CeA GABAergic responses were elevated and N/OFQ exerted a larger inhibition of IPSPs compared with unrestraint rats. The NOP antagonist [Nphe1]-nociceptin(1-13)NH2 increased the IPSP amplitudes in restraint rats but not in unrestraint rats, suggesting a functional recruitment of the N/OFQ system after acute stress. Finally, we evaluated the anxiety-like response in rats subjected to restraint stress and nonrestraint rats after N/OFQ microinjection into the CeA. Intra-CeA injections of N/OFQ significantly and selectively reduced anxiety-like behavior in restraint rats in the elevated plus maze. These combined results demonstrate that acute stress increases N/OFQ systems in the CeA and that N/OFQ has antistress properties.
authors.affiliation: School of Pharmacy, Pharmacology Unit, University of Camerino, Camerino 62032, Italy, Institute of Psychopharmacology at the Central Institute of Mental Health, Medical Faculty Mannheim/University of Heidelberg, Heidelberg 68159, Germany, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland 20892-1108.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ciccocioppo
authors.forename: Giordano
authors.initials: G
authors.lastname: de Guglielmo
authors.forename: Anita C
authors.initials: AC
authors.lastname: Hansson
authors.forename: Massimo
authors.initials: M
authors.lastname: Ubaldi
authors.forename: Marsida
authors.initials: M
authors.lastname: Kallupi
authors.forename: Maureen T
authors.initials: MT
authors.lastname: Cruz
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Oleata
authors.forename: Markus
authors.initials: M
authors.lastname: Heilig
authors.forename: Marisa
authors.initials: M
authors.lastname: Roberto
mesh_terms: D000679:Amygdala / Q000378:metabolism*; D000818:Animals; D001007:Anxiety / Q000378:metabolism*; D001522:Behavior, Animal / Q000502:physiology*; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004195:Disease Models, Animal; D017403:In Situ Hybridization; D008297:Male; D018847:Opioid Peptides / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D051381:Rats; D017208:Rats, Wistar; D012149:Restraint, Physical; D013315:Stress, Psychological / Q000378:metabolism; D059467:Transcriptome; D000097629:Nociceptin
chemical_list: D003346:Corticotropin-Releasing Hormone; D018847:Opioid Peptides; D000097629:Nociceptin