The novel δ opioid receptor agonist KNT-127 produces distinct anxiolytic-like effects in rats without producing the adverse effects associated with benzodiazepines

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.