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

Novokinin (Arg-Pro-Leu-Lys-Pro-Trp) is a vasorelaxing and hypotensive peptide acting through the angiotensin AT(2) receptor. Centrally administrated novokinin (30nmol/mouse) inhibited the antinociceptive effect of micro 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 (0.01nmol/mouse, i.c.v.) and [p-aminophenylalanine(6)]-angiotensin II [p-NH(2)Phe(6)]-Ang II (0.1nmol/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 kappa or delta agonists. Novokinin, angiotensin II and [p-NH(2)Phe(6)]-Ang did not have affinity for the micro 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.