PI3Kγ mediates the peripheral antinociceptive action of KOR agonists. (A) Mechanical hyperalgesia in rats was induced by an ipl. injection of PGE2 (100 ng/paw). The antinociceptive effect of U50488 (10 μg/paw, 2 h after PGE2 injection) after PGE2-induced hyperalgesia was prevented by treatment with a selective inhibitor of PI3Kγ (30 μg/paw, 30 min before the U50488 injection). (B) Mechanical hyperalgesia was induced by the injection of PGE2 (30 ng/paw). After 30 min, U50488 (3 μg/paw) or saline (25 μl) (indicated by the arrow) was injected in wild type or PI3Kγ-/- mice. (C) Thermal hyperalgesia was induced in mice by the injection of PGE2 (300 ng/paw). After 15 min, U50488 (10 μg/paw) was injected in the ipsilateral paws of wild type (WT) or PI3Kγ-/- mice (n = 6). Thermal hyperalgesia was evaluated 1 h after PGE2 injection. (D) Mice received an intraplantar injection of CFA (10 μl/paw). After 4 h, U50488 (3 μg/paw) or saline (Sal) was injected in the wild type or PI3Kγ-/- mice. Data are expressed as the mean ± S.E.M. of 5-6 animals per group. * Indicates statistical significance compared to the vehicle group. # Indicates statistical significance compared to the U50488 treated group or wild type group. P < 0.05, one-way ANOVA, followed by the Bonferroni correction.