Angiotensin AT2 receptor agonists act as anti-opioids via EP3 receptor in mice

Novokinin (Arg-Pro-Leu-Lys-Pro-Trp) is a vasorelaxing and hypotensive peptide acting through the angiotensin AT2 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 AT2 receptor. Angiotensin II (0.01 nmol/mouse, i.c.v.) and [p-aminophenylalanine6]-angiotensin II [p-NH2Phe6]-Ang II (0.1 nmol/mouse, i.c.v.), a highly selective AT2 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-NH2Phe6]-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 EP3 receptor. These results suggest that the anti-opioid effects of AT2 agonists are mediated by the PGE2-EP3 receptor system downstream of the AT2 receptor.