title: Endogenous nociceptin/orphanin FQ signalling produces opposite spinal antinociceptive and supraspinal pronociceptive effects in the mouse formalin test: pharmacological and genetic evidences.
abstract: Nociceptin/orphanin FQ (N/OFQ) has been demonstrated to modulate nociceptive transmission via selective activation of N/OFQ peptide (NOP) receptors. Despite huge research efforts, the role(s) of the endogenous N/OFQ-NOP receptor system in pain processing remains incompletely understood. In the present study, we investigated the role of endogenous N/OFQ in the processing of tonic nociceptive input. To address this issue the effects of NOP-selective antagonists [Nphe1,Arg14,Lys15]N/OFQ-NH2 (UFP-101) and J-113397 on nociceptive behaviour, and the nociceptive phenotype of NOP receptor-deficient mice were tested in the mouse formalin test. Twenty microliters of 1.5% formalin solution was injected subcutaneously into the right hind paw causing a characteristic pattern of nociceptive behaviours (licking, biting and lifting of the injected paw). In control mice, the injection of formalin resulted in a classical biphasic nociceptive response with the first phase lasting from 0 to 10 min and the second phase from 15 to 45 min. UFP-101 at 10 nmol/mouse (but not at 1 nmol/mouse) produced antinociceptive action when injected intracerebroventricularly and a pronociceptive action when given intrathecally. Systemic administration of J-113397 (10 mg/kg, intravenously) and the genetic ablation of the NOP receptor gene both produced a significant increase of mouse nociceptive behaviour. Collectively, these results demonstrate that endogenous N/OFQ-NOP receptor signalling is activated during the mouse formalin test producing spinal antinociceptive and supraspinal pronociceptive effects. The overall effect of blocking NOP receptor signalling, by either systemic pharmacological antagonism or genetic ablation, indicates that the spinal antinociceptive action prevails over supraspinal pronociceptive effects.
authors.affiliation: Department of Experimental and Clinical Medicine, Section of Pharmacology and Neuroscience Center, University of Ferrara, via Fossato di Mortara 19, 44100 Ferrara, Italy. a.rizzi@unife.it
authors.forename: Anna
authors.initials: A
authors.lastname: Rizzi
authors.forename: Cristiano
authors.initials: C
authors.lastname: Nazzaro
authors.forename: G Giuliano
authors.initials: GG
authors.lastname: Marzola
authors.forename: Silvia
authors.initials: S
authors.lastname: Zucchini
authors.forename: Claudio
authors.initials: C
authors.lastname: Trapella
authors.forename: Remo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Hanns Ulrich
authors.initials: HU
authors.lastname: Zeilhofer
authors.forename: Domenico
authors.initials: D
authors.lastname: Regoli
authors.forename: Girolamo
authors.initials: G
authors.lastname: Calo'
mesh_terms: D000700:Analgesics / Q000627:therapeutic use*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal; D001562:Benzimidazoles / Q000008:administration & dosage; D004347:Drug Interactions; D005557:Formaldehyde / Q000009:adverse effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000008:administration & dosage / Q000502:physiology*; D010146:Pain / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D010147:Pain Measurement / Q000379:methods; D010880:Piperidines / Q000008:administration & dosage; D011930:Reaction Time / Q000187:drug effects; D011957:Receptors, Opioid / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects*; D013116:Spinal Cord / Q000187:drug effects / Q000503:physiopathology; D013997:Time Factors; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D001562:Benzimidazoles; D005557:Formaldehyde; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010880:Piperidines; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C479838:(Nphe(1),Arg(14),Lys(15))N-OFQ NH(2); C402921:J 113397; C000722287:Oprl1 protein, mouse