Rubiscolin-6 rapidly suppresses the postprandial motility of the gastric antrum and subsequently increases food intake via δ-opioid receptors in mice

Rubiscolin-6 is a food-derived opioid peptide found in Spinacia oleracea that has anti-nociceptive, memory-enhancing, anxiolytic-like and anti-depressant effects. Rubiscolin-6 has been reported to have two opposing effects on food intake. Food intake is closely connected to gut motility; however, to the best of our knowledge, the effect of rubiscolin-6 on gut motility has not been reported. The present study aimed to investigate the effect of rubiscolin-6 on postprandial motility of the gastric antrum in conscious mice. A catheter was implanted in the gastric antrum of male C57BL/6J mice. Manometric measurements were performed in fasted male mice and chow was then provided to assess motility in the fed state. Rubiscolin-6, the δ-opioid receptor antagonist naltrindole, a mixture of rubiscolin-6 and naltrindole, or vehicle was administered intraperitoneally 30 min after eating. The percentage motor index (%MI) was then calculated. Cumulative food intake was measured in both ad libitum-fed and overnight-fasted mice. The %MI was significantly lower in mice treated with rubiscolin-6 compared with that in the other groups, but normalized by treatment with the rubiscolin-6/naltrindole mixture. The decrease in %MI induced by rubiscolin-6 remained for 1 h after administration. Cumulative food intake was significantly higher 4 and 6 h after rubiscolin-6 administration in ad libitum-fed mice but was normalized by the rubiscolin-6/naltrindole mixture. Food intake 30 min after rubiscolin-6 administration was normal, but was higher in mice treated with the rubiscolin-6/naltrindole mixture. Thus, rubiscolin-6 may have a rapid effect to reduce postprandial antral motility and may subsequently increase food intake after this inhibitory effect disappears. These effects were revealed to be mediated through δ-opioid receptors. The orexigenic effect of rubiscolin-6 may be applicable to the treatment of anorexia and cachexia.