title: Antinociceptive effects of spinally administered nociceptin/orphanin FQ and its N-terminal fragments on capsaicin-induced nociception.
abstract: Nociceptin/orphanin FQ (N/OFQ), the endogenous ligand for the N/OFQ peptide (NOP) receptors, has been shown to be metabolized into some fragments. We examined to determine whether intrathecal (i.t.) N/OFQ (1-13), (1-11) and (1-7) have antinociceptive activity in the pain-related behavior after intraplantar injection of capsaicin. The i.t. administration of N/OFQ (0.3-1.2 nmol) produced an appreciable and dose-dependent inhibition of capsaicin-induced paw-licking/biting response. The N-terminal fragments of N/OFQ, (1-13) and (1-11), were antinociceptive with a potency lower than N/OFQ. Calculated ID₅₀ values (nmol, i.t.) were 0.83 for N/OFQ, 2.5 for N/OFQ (1-13) and 4.75 for N/OFQ (1-11), respectively. The time-course effect revealed that the antinociceptive effects of these N-terminal fragments lasted longer than those of N/OFQ. Removal of amino acids down to N/OFQ (1-7) led to be less potent than N/OFQ and its fragments, (1-13) and (1-11). Antinociception induced by N/OFQ or N/OFQ (1-13) was reversed significantly by i.t. co-injection of [Nphe¹]N/OFQ (1-13)NH₂, a peptidergic antagonist for NOP receptors, whereas i.t. injection of the antagonist did not interfere with the action of N/OFQ (1-11) and (1-7). Pretreatment with the opioid receptor antagonist naloxone hydrochloride did not affect the antinociception induced by N/OFQ and its N-terminal fragments. These results suggest that N-terminal fragments of N/OFQ are active metabolites and may modulate the antinociceptive effect of N/OFQ in the spinal cord. The results also indicate that N/OFQ (1-13) still possess antinociceptive activity through NOP receptors.
authors.affiliation: Department of Pharmacology, Daiichi College of Pharmaceutical Sciences, 22-1 Tamagawa-cho, Minami-ku, Fukuoka 815-8511, Japan.
authors.forename: Soh
authors.initials: S
authors.lastname: Katsuyama
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Mizoguchi
authors.forename: Takaaki
authors.initials: T
authors.lastname: Komatsu
authors.forename: Chikai
authors.initials: C
authors.lastname: Sakurada
authors.forename: Minoru
authors.initials: M
authors.lastname: Tsuzuki
authors.forename: Shinobu
authors.initials: S
authors.lastname: Sakurada
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Sakurada
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D001522:Behavior, Animal; D002211:Capsaicin / Q000009:adverse effects / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D020128:Inhibitory Concentration 50; D007278:Injections, Spinal; D007279:Injections, Subcutaneous; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009270:Naloxone / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D010146:Pain / Q000188:drug therapy* / Q000503:physiopathology; D010147:Pain Measurement / Q000187:drug effects* / Q000523:psychology; D058748:Pain Perception / Q000187:drug effects* / Q000502:physiology; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use; D011957:Receptors, Opioid / Q000378:metabolism; D013116:Spinal Cord / Q000187:drug effects* / Q000502:physiology; D013329:Structure-Activity Relationship; D000097629:Nociceptin
chemical_list: D000700:Analgesics; D002211:Capsaicin; D009270:Naloxone; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010446:Peptide Fragments; D011957:Receptors, Opioid; D000097629:Nociceptin