Naringenin (2S)-5,7-dihydroxy-2-(4-hydroxyphenyl)-3,4-dihydro-2H-1-benzopyran-4-one is a natural flavonoid found in fruits from the citrus family. Because (2S)-naringenin is known to racemize, its bioactivity might be related to one or both enantiomers. Computational studies predicted that (2R)-naringenin may act on voltage-gated ion channels, particularly the N-type calcium channel (CaV2.2) and the NaV1.7 sodium channel-both of which are key for pain signaling. Here we set out to identify the possible mechanism of action of naringenin. Naringenin inhibited depolarization-evoked Ca2+ influx in acetylcholine-, ATP-, and capsaicin-responding rat dorsal root ganglion (DRG) neurons. This was corroborated in electrophysiological recordings from DRG neurons. Pharmacological dissection of each of the voltage-gated Ca2+ channels subtypes could not pinpoint any selectivity of naringenin. Instead, naringenin inhibited NaV1.8-dependent and tetrodotoxin (TTX)-resistant while sparing tetrodotoxin sensitive (TTX-S) voltage-gated Na+ channels as evidenced by the lack of further inhibition by the NaV1.8 blocker A-803467. The effects of the natural flavonoid were validated ex vivo in spinal cord slices where naringenin decreased both the frequency and amplitude of sEPSC recorded in neurons within the substantia gelatinosa. The antinociceptive potential of naringenin was evaluated in male and female mice. Naringenin had no effect on the nociceptive thresholds evoked by heat. Naringenin's reversed allodynia was in mouse models of postsurgical and neuropathic pain. Here, driven by a call by the National Center for Complementary and Integrative Health's strategic plan to advance fundamental research into basic biological mechanisms of the action of natural products, we advance the antinociceptive potential of the flavonoid naringenin.

中文翻译：

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天然类黄酮柚皮素通过抑制NaV1.8电压门控钠通道而引起镇痛作用。

柚皮素（2S）-5,7-二羟基-2-（4-羟基苯基）-3,4-二氢-2H-1-苯并吡喃-4-酮是一种天然的类黄酮，存在于柑橘类水果中。由于已知（2S）-柚皮素具有消旋作用，因此其生物活性可能与一种或两种对映异构体有关。计算研究预测（2R）-柚皮苷可能作用于电压门控离子通道，特别是N型钙通道（CaV2.2）和NaV1.7钠通道，这两个通道都是疼痛信号的关键。在这里，我们着手确定柚皮苷的可能作用机理。柚皮素抑制乙酰胆碱，ATP和辣椒素反应的大鼠背根神经节（DRG）神经元的去极化诱发的Ca2 +流入。DRG神经元的电生理记录证实了这一点。每种电压门控性Ca2 +通道亚型的药理分析都无法确定柚皮苷的任何选择性。相反，柚皮苷抑制NaV1.8依赖性和河豚毒素（TTX）的耐药性，同时保留河豚毒素敏感（TTX-S）电压门控的Na +通道，这由NaV1.8受体阻滞剂A-803467缺乏进一步的抑制作用来证明。天然黄酮的作用在脊髓切片中得到了体外验证，其中柚皮苷降低了明胶质神经元中sEPSC的频率和幅度。在雄性和雌性小鼠中评估了柚皮苷的抗伤害感受能力。柚皮素对热引起的伤害阈值没有影响。Naringenin的异常性疼痛逆转是在术后和神经性疼痛的小鼠模型中。这里，