Pinho-Ribeiro Felipe A, Zarpelon Ana C, Fattori Victor, Manchope Marília F, Mizokami Sandra S, Casagrande Rubia, Verri Waldiceu A
Departamento de Ciências Patológicas-Centro de Ciências Biológicas, Universidade Estadual de Londrina, 86057970 Londrina, Brazil.
Departamento de Ciências Farmacêuticas - Centro de Ciências de Saúde, Universidade Estadual de Londrina, 86039440 Londrina, Brazil.
Neuropharmacology. 2016 Jun;105:508-519. doi: 10.1016/j.neuropharm.2016.02.019. Epub 2016 Feb 18.
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.
柚皮素是一种人类广泛摄入的黄酮类化合物，具有抗炎活性且毒性较低。最近，柚皮素在神经性疼痛模型中已被证明具有镇痛作用。在此，我们测试了柚皮素在几种炎性疼痛模型中的镇痛效果。在注射炎性刺激物之前，小鼠接受柚皮素（16.7 - 150毫克/千克，口服）或对照抗炎药物吲哚美辛（5毫克/千克，腹腔注射）或安乃近（80毫克/千克，腹腔注射）的治疗。对于急性疼痛，我们使用乙酸和PBQ诱导的内脏疼痛（腹部扭体），以及福尔马林、辣椒素和CFA诱导的爪部退缩和舔舐。通过使用电子版的von Frey细丝，我们还研究了柚皮素对角叉菜胶、辣椒素、CFA或前列腺素E2足底注射后对机械刺激的疼痛强度（机械性痛觉过敏）的影响。柚皮素（50毫克/千克）减少了所有测试刺激诱导的急性疼痛行为，包括福尔马林试验的两个阶段，这表明该化合物除了具有抗炎活性外，还具有直接的伤害感受器调节作用。因此，柚皮素还抑制了角叉菜胶、辣椒素和前列腺素E2诱导的对机械刺激的敏感性增加。连续7天每天用柚皮素治疗也减少了CFA诱导的机械性痛觉过敏，且无胃或肝毒性。柚皮素的作用机制包括抑制角叉菜胶诱导的氧化应激、痛觉过敏细胞因子（IL - 33、TNF -α和IL - 1β）的产生以及爪部皮肤中NF -κB的激活。柚皮素还激活了镇痛的NO - 环鸟苷酸 - 蛋白激酶G - ATP敏感钾（+）通道信号通路，以抑制角叉菜胶诱导的机械性痛觉过敏和中性粒细胞募集。这些结果表明柚皮素可抑制炎性疼痛和神经源性炎症。
