title: Characterization of nociceptin/orphanin FQ-induced pain responses by the novel receptor antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride.
abstract: At the spinal level, nociceptin/orphanin FQ (Noc/OFQ) produces pronociceptive and allodynic effects at low doses (picogram range), while causing antinociceptive effects at high doses (microgram range). The discrepancy of pain modulation by Noc/OFQ at low and high doses raised a question whether Noc/OFQ exerted actions through the same Noc/OFQ receptor. In the present study, we examined the involvement of the Noc/OFQ receptor in pain responses with the novel nonpeptide antagonist N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl) benzamide monohydrochloride (JTC-801). Allodynia and hyperalgesia evoked by intrathecal administration of Noc/OFQ (50 pg/mouse) were dose dependently blocked by simultaneous administration of JTC-801 with IC(50) values of 32.2 and 363 pg, respectively. JTC-801 did not induce allodynia by itself. Subcutaneous injection of formalin into a hindpaw evoked biphasic pain behaviors such as flinching and biting in mice. Noc/OFQ at 10 pg increased the second-phase pain behaviors evoked by 1% formalin, whereas it strongly inhibited both the first-phase and second-phase pain evoked by 2% formalin at 1 microg. Although the pronociceptive effect by 10 pg of Noc/OFQ was dose dependently blocked by JTC-801 with an IC(50) value of 4.58 pg, the antinociceptive effects by 1 microg of Noc/OFQ were not antagonized by JTC-801. Furthermore, both phases of 2% formalin-induced pain behaviors were relieved by JTC-801. These results demonstrate that pronociceptive responses induced by a low dose of Noc/OFQ may be mediated through the Noc/OFQ receptor in the spinal cord and that JTC-801 can be a useful antagonist to examine the involvement of endogenous Noc/OFQ and mediation of the Noc/OFQ receptor under physiological and pathophysiological conditions including pain.
authors.affiliation: Department of Anesthesiology, Osaka Medical College, Takatsuki, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Muratani
authors.forename: Toshiaki
authors.initials: T
authors.lastname: Minami
authors.forename: Utako
authors.initials: U
authors.lastname: Enomoto
authors.forename: Masato
authors.initials: M
authors.lastname: Sakai
authors.forename: Emiko
authors.initials: E
authors.lastname: Okuda-Ashitaka
authors.forename: Kimihiro
authors.initials: K
authors.lastname: Kiyokane
authors.forename: Hidemaro
authors.initials: H
authors.lastname: Mori
authors.forename: Seiji
authors.initials: S
authors.lastname: Ito
mesh_terms: D000634:Aminoquinolines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D006930:Hyperalgesia / Q000139:chemically induced*; D007278:Injections, Spinal; D007700:Kinetics; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010146:Pain / Q000139:chemically induced / Q000503:physiopathology*; D011957:Receptors, Opioid / Q000502:physiology*; D000094942:Nociceptin Receptor; D000097629:Nociceptin
chemical_list: D000634:Aminoquinolines; D001549:Benzamides; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D011957:Receptors, Opioid; D000094942:Nociceptin Receptor; D000097629:Nociceptin; C433236:N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxymethyl)benzamide; C000722287:Oprl1 protein, mouse