Naringenin reduces inflammatory pain in mice

Naringenin is a flavonoid widely consumed by humans that present anti-inflammatory activity and low toxicity. Recently, the analgesic effect of naringenin has been demonstrated in neuropathic pain models. Herein, we tested the analgesic effects of naringenin in several models of inflammatory pain. Mice received treatment with naringenin (16.7-150 mg/kg, per oral), or with the controls anti-inflammatory drugs indomethacin (5 mg/kg, intraperitoneal) or dipyrone (80 mg/kg, intraperitoneal) prior the inflammatory stimuli injection. For acute pain, we used acetic acid- and PBQ-induced visceral pain (abdominal writhings), and formalin-, capsaicin-, and CFA-induced paw flinching and licking. By using an electronic version of von Frey filaments, we also investigated the effects of naringenin in pain intensity to a mechanical stimulus (mechanical hyperalgesia) after carrageenan, capsaicin, CFA, or PGE2 intraplantar injection. Naringenin (50 mg/kg) reduced acute pain behaviors induced by all tested stimuli, including both phases of formalin test, suggesting a direct nociceptor modulatory effect of this compound besides its anti-inflammatory activity. Accordingly, naringenin also inhibited the increased sensitivity to mechanical stimulus induced by carrageenan, capsaicin, and PGE2. Daily treatment with naringenin during 7 days also reduced CFA-induced mechanical hyperalgesia without gastric or hepatic toxicity. The mechanisms of naringenin involve the inhibition of carrageenan-induced oxidative stress, hyperalgesic cytokines (IL-33, TNF-α, and IL-1β) production and NF-κB activation in the paw skin. Naringenin also activated the analgesic NO-cyclic GMP-PKG-ATP sensitive K+ channel signaling pathway to inhibit carrageenan-induced mechanical hyperalgesia and neutrophil recruitment. These results suggest that naringenin inhibits both inflammatory pain and neurogenic inflammation.