title: The novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats without producing the adverse effects associated with benzodiazepines.
abstract: We previously reported that a δ opioid receptor agonist SNC80 produced potent anxiolytic-like effects in rodents. Recently, we succeeded in synthesizing a novel δ opioid receptor agonist KNT-127. In this study, we investigated the anxiolytic-like effects of KNT-127 using three different rat models of innate anxiety. In an elevated plus-maze test, KNT-127 (0.3, 1, and 3.0 mg/kg, s.c.) significantly and dose-dependently increased the time rats spent in the open arms 30 min after administration. The magnitude of the KNT-127 (3.0 mg/kg, s.c.)-induced anxiolytic-like effects was similar to that produced by diazepam (1.0 mg/kg, s.c.), a benzodiazepine anxiolytic. The anxiolytic-like effects of KNT-127 (3.0 mg/kg, s.c.) were abolished by pretreatment with naltrindole (0.1 mg/kg, s.c.), a selective δ opioid receptor antagonist, suggesting that KNT-127-induced anxiolytic-like effects are mediated by δ opioid receptors. These findings were supported by results obtained from light/dark and open-field tests. Interestingly, in contrast to diazepam (1.0 mg/kg, s.c.), KNT-127 (3.0 mg/kg, s.c.) caused no significant performance changes in the Y-maze test, the ethanol-induced sleeping test, and footprint test. This is the first study to demonstrate that the novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats, without producing the adverse effects associated with benzodiazepines.
authors.affiliation: Department of Neuropsychopharmacology, National Institute of Mental Health, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashimachi, Kodaira, Tokyo 187-8553, Japan. asaitoh@ncnp.go.jp
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Saitoh
authors.forename: Azusa
authors.initials: A
authors.lastname: Sugiyama
authors.forename: Misa
authors.initials: M
authors.lastname: Yamada
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Inagaki
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Oka
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Yamada
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000009:adverse effects* / Q000494:pharmacology*; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D009019:Morphinans / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000502:physiology; D012890:Sleep / Q000187:drug effects / Q000502:physiology
chemical_list: D014151:Anti-Anxiety Agents; C555233:KNT 127; D009019:Morphinans; D017465:Receptors, Opioid, delta; D001569:Benzodiazepines