The natural flavonoid Naringenin elicits analgesia through inhibition of NaV1.8 voltage-gated sodium channels.
ACS Chem Neurosci. 2019 Nov 7. Epub 2019 Nov 7. PMID: 31697467
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. Since (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 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, 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 post-surgical and neuropathic pain. Here, driven by a call by the NCCIH's strategic plan to advance fundamental research into basic biological mechanisms of action of natural products, we advance the antinociceptive potential of the flavonoid Naringenin.