Rubiscolin-6, a δ opioid peptide derived from spinach Rubisco, has anxiolytic effect via activating σ1 and dopamine D1 receptors

Abstract Rubiscolin-6 (Tyr-Pro-Leu-Asp-Leu-Phe) is a δ opioid peptide derived from the large subunit of spinach d -ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). We previously reported that rubiscolin-6 had an analgesic effect and stimulated memory consolidation. Here we show that intraperitoneally (i.p.) or orally administered rubiscolin-6 has an anxiolytic effect at a dose of 10 mg/kg or 100 mg/kg, respectively, in the elevated plus-maze test in mice. The anxiolytic effects of rubscolin-6 after i.p. (10 mg/kg) and oral (100 mg/kg) administration were blocked by a δ opioid receptor antagonist, naltrindole (1 mg/kg, s.c.), suggesting that the anxiolytic activity of rubiscolin-6 is mediated by δ opioid receptor. The anxiolytic effect of rubiscolin-6 (10 mg/kg, i.p.) was also blocked by a dopamine D 1 antagonist, SCH23390 (30 μg/kg, i.p.), but not by a dopamine D 2 antagonist, raclopride (15 μg/kg, i.p.). The anxiolytic effect of rubiscolin-6 (10 mg/kg, i.p.) was blocked by σ 1 receptor antagonist, BMY14802 (0.5 mg/kg, i.p.) or BD1047 (10 mg/kg, i.p.). Taken together, the anxiolytic effect of rubiscolin-6 is mediated by σ 1 and dopamine D 1 receptors downstream of δ opioid receptor.