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 Phamacopoeia, while the mechanisms behind these effects have not been fully explored. Among the hundred 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 current and dampen excitability of DRG neuron, while LCB did not show inhibition effect on Na_V current. 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 phase1 and phase2 of formalin test and LCB can inhibit the pain responses during phase2. 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 In this study, we found LCA can inhibit Na_V currents and dampen excitabilities of DRG neurons and inhibit the Na_V1.7 channels exogenously expressed in HEK293T cells. Animal behaviour tests showed that LCA can inhibit the pain responses during phase1 and phase2 of formalin test while LCB can inhibit the pain responses during phase2. These findings indicate that licochalcones could be the leading compounds for developing Na_V channel inhibitors and effective analgesic medicines.