title: Swim stress enhances nociceptin/orphanin FQ-induced inhibition of rat dorsal raphe nucleus activity in vivo and in vitro: role of corticotropin releasing factor.
abstract: The effects of nociceptin/orphanin FQ on putative serotonin (5HT) neurons of the dorsal raphe nucleus (DRN), known to modulate the behavioral responses to stress, were investigated in vivo and in vitro. In DRN slices from unstressed rats, nociceptin/orphanin FQ concentration-dependently inhibited the firing rate of putative 5HT neurons (EC(50) = 21.6 +/- 1.21 nM) and the selective NOP receptor antagonist UFP-101 shifted the concentration-response curve to the right (estimated pA(2) 6.86). Nociceptin/orphanin FQ potency was enhanced in slices prepared from rats previously subjected to a 15 min swim stress (EC(50) = 1.98 +/- 0.11 nM). Swim stress did not change the number or affinity of NOP receptors in DRN. Stress-elicited potentiation involved corticotropin-releasing factor (CRF)(1) receptors, GABA signaling and protein synthesis, being attenuated by pre-treatment with antalarmin (20 mg/kg, i.p.), diazepam (2.4 mg/kg, i.p.) and cycloheximide (2.5 mg/kg, i.p.), respectively. In anesthetized unstressed rats, locally applied nociceptin/orphanin FQ (0.03 and 0.1 ng/30 nl) inhibited the firing rate of DRN neurons (to 80 +/- 7 and 54 +/- 10% of baseline, respectively). Nociceptin/orphanin FQ inhibition was potentiated both 24 h after swim stress and 1 h after CRF (30 ng/30 nl intra-DRN). Stress-induced potentiation was prevented by the selective CRF(1) receptor antagonist, NBI 30755 (20 mg/kg, i.p.). In contrast, the inhibitory response of DRN neurons to the 5HT(1A) agonist, 8OH-DPAT (1 microg/1 microl, intra-DRN) was not potentiated by swim stress, ruling out a non-specific enhanced permeability of GIRK channel. Together, these findings suggest that CRF and the nociceptin/orphanin FQ/NOP system interact in the DRN during stress to control 5HT transmission; this may play a role in stress-related neuropsychopathologies.
authors.affiliation: Department of Clinical and Experimental Medicine, Section Pharmacology, University of Ferrara, via Fossato di Mortara 17-19, 44100-Ferrara, Italy.
authors.forename: Cristiano
authors.initials: C
authors.lastname: Nazzaro
authors.forename: Mario
authors.initials: M
authors.lastname: Barbieri
authors.forename: Katia
authors.initials: K
authors.lastname: Varani
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Beani
authors.forename: Rita J
authors.initials: RJ
authors.lastname: Valentino
authors.forename: Anna
authors.initials: A
authors.lastname: Siniscalchi
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D066298:In Vitro Techniques; D008297:Male; D009292:Narcotic Antagonists; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018847:Opioid Peptides / Q000378:metabolism*; D011903:Raphe Nuclei / Q000187:drug effects / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism; D018019:Receptors, Corticotropin-Releasing Hormone / Q000037:antagonists & inhibitors / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism; D058825:Serotonin 5-HT1 Receptor Agonists; D013315:Stress, Psychological / Q000503:physiopathology*; D013550:Swimming; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism; D000094942:Nociceptin Receptor; D000097629:Nociceptin; D000099052:CRF Receptor, Type 1
chemical_list: D003346:Corticotropin-Releasing Hormone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D044282:Receptor, Serotonin, 5-HT1A; D018019:Receptors, Corticotropin-Releasing Hormone; D011957:Receptors, Opioid; D012701:Serotonin; D058825:Serotonin 5-HT1 Receptor Agonists; D005680:gamma-Aminobutyric Acid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; D000099052:CRF Receptor, Type 1; C000722285:Oprl1 protein, rat