title: Pronociceptive effects of nociceptin/orphanin FQ (13-17) at peripheral and spinal level in mice.
abstract: The heptadecapeptide nociceptin/orphanin FQ (N/OFQ) is reported to be metabolized by aminopeptidase N and endopeptidase 24.15. In the present study, N/OFQ C-terminal fragments elicited nociceptive responses in the peripheral nociceptors and in the spinal cord, whereas N-terminal fragments had no significant nociception. The nociceptive effect of N/OFQ (13-17) was most potent and remained unchanged in N/OFQ peptide receptor (NOPR) gene knockout mice, indicating that N/OFQ (13-17)-induced nociception is mediated through a novel mechanism independent of the activation of NOPR. This finding was further confirmed by in vitro guanosine 5'-O-(3-[35S]thio)triphosphate binding experiments, in which N/OFQ (13-17) showed no significant binding activity in baculovirus/sf21 cells expressing NOPR together with G protein alpha(i)1-, beta1-, and gamma2-subunits, whereas N/OFQ showed stimulation in a concentration-dependent manner. On the other hand, although a typical bell-shaped dose-response relationship was observed with a wide range of N/OFQ doses in both peripheral and central nociception tests, N/OFQ (13-17) did not show bell-shaped dose-response relationship in the central nociception test. This finding indicates that N/OFQ (13-17), in contrast to N/OFQ, lacks the postsynaptic antinociceptive actions modulating substance P signaling in the spinal cord. Together, our results suggest that C-terminal fragments of N/OFQ have potent nociceptive actions, and N/OFQ (13-17) could have the potential to mediate its actions through a novel mechanism independent of the activation of NOPR in the nociceptors and in spinal synapses.
authors.affiliation: Department of Molecular Pharmacology and Neuroscience, Nagasaki University School of Pharmaceutical Sciences, Nagasaki, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Inoue
authors.forename: S
authors.initials: S
authors.lastname: Matsunaga
authors.forename: M H
authors.initials: MH
authors.lastname: Rashid
authors.forename: A
authors.initials: A
authors.lastname: Yoshida
authors.forename: K
authors.initials: K
authors.lastname: Mizuno
authors.forename: T
authors.initials: T
authors.lastname: Sakurada
authors.forename: H
authors.initials: H
authors.lastname: Takeshima
authors.forename: H
authors.initials: H
authors.lastname: Ueda
mesh_terms: D000818:Animals; D016367:Baculoviridae / Q000235:genetics; D002211:Capsaicin / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D009154:Mutation; D015288:Neurokinin A / Q000494:pharmacology; D009619:Nociceptors / Q000187:drug effects*; D018847:Opioid Peptides / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D010525:Peripheral Nerves / Q000187:drug effects*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: C417048:(F-G)NOC oFQ(1-13)-NH2; D018847:Opioid Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D010566:Virulence Factors, Bordetella; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015288:Neurokinin A; D002211:Capsaicin