Bradykinin induces peripheral antinociception in PGE₂-induced hyperalgesia in mice

Bradykinin (BK) is an endogenous peptide involved in vascular permeability and inflammation. It has opposite effects (inducing hyperalgesia or antinociception) when administered directly in the central nervous system. The aim of this study was to evaluate whether BK may also present this dual effect when injected peripherally in a PGE₂-induced nociceptive pain model, as well as to investigate the possible mechanisms of action involved in this event in mice.

Male Swiss and C57BL/6 knockout mice for B₁ or B₂ bradykinin receptors were submitted to a mechanical paw pressure test and hyperalgesia was induced by intraplantar prostaglandin E₂ (2 µg/paw) injection.

Bradykinin (20, 40 and 80 ng/paw) produced dose-dependent peripheral antinociception against PGE₂-induced hyperalgesia. This effect was antagonized by bradyzide (8, 16 and 32 μg/paw), naloxone (12.5, 25 and 50 μg/paw), nor-binaltorphimine (50, 100 and 200 μg/paw) and AM251 (20, 40 and 80 μg/paw). Bestatin (400 µg/paw), MAFP (0.5 µg/paw) and VDM11 (2.5 µg/paw) potentiated the antinociception of a lower 20 ng BK dose. The knockout of B₁ or B₂ bradykinin receptors partially abolished the antinociceptive action of BK (80 ng/paw), bremazocine (1 μg/paw) and anandamide (40 ng/paw) when compared with wild-type animals, which show complete antinociception with the same dose of each drug.

The present study is the first to demonstrate BK-induced antinociception in peripheral tissues against PGE₂-induced nociception in mice and the involvement of κ-opioid and CB₁ cannabinoid receptors in this effect.