Licochalcone Mediates the Pain Relief by Targeting the Voltage-Gated Sodium Channel

Licorice is a traditional Chinese medicine and recorded to have pain relief effects in national pharmacopoeia, but the mechanisms behind these effects have not been fully explored. Among the hundreds of compounds in licorice, licochalcone A (LCA) and licochalcone B (LCB) are two important components belonging to the chalcone family. In this study, we compared the analgesic effects of these two licochalcones and the molecular mechanisms. LCA and LCB were applied in cultured dorsal root ganglion (DRG) neurons, and the voltage-gated sodium (Na_V) currents and action potentials were recorded. The electrophysiological experiments showed that LCA can inhibit Na_V currents and dampen excitabilities of DRG neurons, whereas LCB did not show inhibition effect on Na_V currents. Because the Na_V1.7 channel can modulate Subthreshold membrane potential oscillations in DRG neuron, which can palliate neuropathic pain, HEK293T cells were transfected with Na_V1.7 channel and recorded with whole-cell patch clamp. LCA can also inhibit Na_V1.7 channels exogenously expressed in HEK293T cells. We further explored the analgesic effects of LCA and LCB on formalin-induced pain animal models. The animal behavior tests revealed that LCA can inhibit the pain responses during phase 1 and phase 2 of formalin test, and LCB can inhibit the pain responses during phase 2. The differences of the effects on Na_V currents between LCA and LCB provide us with the basis for developing Na_V channel inhibitors, and the novel findings of analgesic effects indicate that licochalcones can be developed into effective analgesic medicines. SIGNIFICANCE STATEMENT: This study found that licochalcone A (LCA) can inhibit voltage-gated sodium (Na_V) currents, dampen excitabilities of dorsal root ganglion neurons, and inhibit the Na_V1.7 channels exogenously expressed in HEK293T cells. Animal behavior tests showed that LCA can inhibit the pain responses during phase 1 and phase 2 of formalin test, whereas licochalcone B can inhibit the pain responses during phase 2. These findings indicate that licochalcones could be the leading compounds for developing Na_V channel inhibitors and effective analgesic medicines.