Angiotensin AT 2 receptor agonists act as anti-opioids via EP 3 receptor in mice

Abstract

Novokinin (Arg-Pro-Leu-Lys-Pro-Trp) is a vasorelaxing and hypotensive peptide acting through the angiotensin AT 2 receptor. Centrally administrated novokinin (30 nmol/mouse) inhibited the antinociceptive effect of μ agonist morphine in mice, as evaluated by the tail-pinch test. The anti-opioid effect of novokinin was blocked by PD123319, an antagonist of the AT 2 receptor. Angiotensin II (0.01 nmol/mouse, i.c.v.) and [ p-aminophenylalanine 6]-angiotensin II [ p-NH 2Phe 6]-Ang II (0.1 nmol/mouse, i.c.v.), a highly selective AT 2 receptor agonist, also inhibited the antinociceptive effect of morphine, and the effects were also blocked by PD123319. Angiotensin II did not suppress the antinociceptive effect induced by κ or δ agonists. Novokinin, angiotensin II and [ p-NH 2Phe 6]-Ang did not have affinity for the μ receptor. The anti-opioid effects induced by these peptides were blocked by ONO-AE3-240, an antagonist of the EP 3 receptor. These results suggest that the anti-opioid effects of AT 2 agonists are mediated by the PGE 2-EP 3 receptor system downstream of the AT 2 receptor.