The Natural Flavonoid Naringenin Elicits Analgesia through Inhibition of NaV1.8 Voltage-Gated Sodium Channels

Abstract

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 Ca 2+ 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 Ca 2+ 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.

Targeting the T-type calcium channel Cav3.2 in GABAergic arcuate nucleus neurons to treat obesity

“…Naringenin, a flavonoid present in sweet oranges and grapefruit, was recently found to improve glucose and lipid homeostasis and mitigate adipose tissue inflammation in rodents and humans [ 27 , [38] , [39] , [40] ]. Naringenin has been shown to interact with voltage-gated ion channels and potentially block VGCCs, including Cav3.2 [ [41] , [42] , [43] ]. We speculated that Cav3.2 expressed by Vgat ARH neurons partially mediates the beneficial metabolic effects of naringenin.…”

“…However, the underlying mechanism in which naringenin modulates energy homeostasis is largely unknown. Recently, naringenin has been found to enter blood–brain barrier (BBB) [ 97 ] and acts as a potential blocker for VGCCs, including Cav3.2 [ [41] , [42] , [43] ], indicating a possible central mechanism through Cav3.2. In our ex vivo brain slice recording study, we found that naringenin decreases the firing activity of Vgat ARH neurons by inhibiting Cav3.2-mediated calcium currents.…”

Therapeutic Potential of Flavonoids in Pain and Inflammation: Mechanisms of Action, Pre-Clinical and Clinical Data, and Pharmaceutical Development

“…In addition, naringenin induces analgesia by blocking TRPM3 and activating TRPM8 [64], which might contribute to its analgesic effect. Naringenin also blocks sodium influx in rat DRG neurons by selecting inhibiting Nav1.8 (and not Nav1.7 or Nav1.9) [65]. Collectively, naringenin targets different channels expressed by neurons and immune cell signaling pathways (decreases NFkB activation and stimulates Nrf2) to reduce pain and inflammation.…”

“…(B) Ion channels expressed by neurons that are targeted by Vitexin, Quercetin, and Naringenin to reduce pain. Vitexin: TRPV1 [38], Quercetin: TRPV1 [63], and Naringenin: TRPV1 [58], TRPA1 [58], TRPM3 [64], Nav 1.8 [65], and TRPM8 [64]. In panel (A), ROS and inflammatory stimuli that activate specific receptors trigger intracellular signaling that will result in pain and inflammation.…”

Synthesis and Evaluation of Novel α-Aminoamides Containing Benzoheterocyclic Moiety for the Treatment of Pain

“…However, specific analgesics for managing chronic pain are an unmet clinic need [1][2][3][4][5]. Voltage-gated sodium ion channels subtype 1.7 (Na v 1.7) and 1.8 (Na v 1.8) have been proven as promising targets for the discovery of new drugs to treat chronic pain and numerous small-molecule inhibitors targeting Na v 1.7 and Na v 1.8 that have been developed in preclinical or clinical studies in recent years [6][7][8][9][10][11][12].…”