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The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels
journal contribution
posted on 2019-11-20, 20:46 authored by Yuan Zhou, Song Cai, Aubin Moutal, Jie Yu, Kimberly Gómez, Cynthia L. Madura, Zhiming Shan, Nancy Y. N. Pham, Maria J. Serafini, Angie Dorame, David D. Scott, Liberty François-Moutal, Samantha Perez-Miller, Marcel Patek, May Khanna, Rajesh KhannaNaringenin (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 channelboth 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.
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Natural Flavonoid Naringenin Elicits Analgesiacapsaicin-responding rat dorsal root ganglionComputational studieselectrophysiological recordingsNational CenterDRG neuronscord slicesneuropathic painvoltage-gated NaTTXsubstantia gelatinosamouse modelsNaV 1.8-dependentTTX-SATPPharmacological dissectionN-type calcium channelflavonoid naringeninNaV 1.8 blockervoltage-gated ion channels
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