Rapakinin, Arg–Ile–Tyr, derived from rapeseed napin, shows anti-opioid activity via the prostaglandin IP receptor followed by the cholecystokinin CCK2 receptor in mice

Rapakinin, Arg–Ile–Tyr, is a vasorelaxing, anti-hypertensive and anorexigenic peptide derived from rapeseed napin. In this study, we found that rapakinin intracerebroventricularly administered to mice inhibited the analgesic effect of morphine, evaluated by the tail-pinch test. The anti-opioid activity of rapakinin was blocked by LY225910, an antagonist of the cholecystokinin (CCK) CCK2 receptor, but not by lorglumide, an antagonist of the CCK1 receptor. The anti-opioid activity of rapakinin was also blocked by CAY10441, an antagonist of the prostaglandin (PG) IP receptor. These results suggest that the anti-opioid activity of rapakinin is mediated by the CCK2 and IP receptors. The anti-opioid activity induced by ciprostene, an IP receptor agonist, was blocked by LY225910, while that of CCK-8 was not blocked by CAY10441. Thus, it is demonstrated that the CCK–CCK2 system was activated downstream of the PGI2–IP receptor system. Taken together, rapakinin shows anti-opioid activity via the activation of the PGI2–IP receptor system followed by the CCK–CCK2 receptor system.

Research highlights▶ Rapakinin, Arg–Ile–Tyr, derived from rapeseed napin, showed anti-opioid activity. ▶ The anti-opioid activity of rapakinin was mediated by cholesystokinin (CCK) and the CCK2 receptor. ▶ The anti-opioid activity of rapakinin was also mediated by prostaglandin I2 and the IP receptor. ▶ CCK–CCK2 system was activated downstream of the PGI2–IP receptor system. ▶ Rapakinin shows anti-opioid activity via the activation of the PGI2–IP receptor system followed by the CCK–CCK2 receptor system.