Glycyrrhiza uralensis Fisch: A novel source of analgesic activity through Na_V1.8 sodium channel modulation

Glycyrrhiza uralensis Fisch. (G. uralensis) is a "medicine food homology" herbal medicine widely used in the pharmaceutical and food industries. G. uralensis has a variety of biological functions, including antioxidant, antiviral, anti-inflammation and analgesic effects. However, the specific mechanism underlying the pain-relieving effects of G. uralensis remains to be explored. Here we investigated the analgesic properties of G. uralensis using rodent models of pain. The crude extracts of G. uralensis effectively alleviated acetic acid-induced inflammatory and paclitaxel-induced neuropathic pain. Further screening studies identified licoisoflavone A as the key bioactive compound of G. uralensis responsible for its analgesic activity, which inhibits the Na_V1.8 sodium channel (IC₅₀ = 7.53 μM). Combining electrophysiological experiments with molecular docking revealed that licoisoflavone A acts as a novel, highly potent pore blocker of the Na_V1.8 channel by obstructing ion flow through the pore region. Moreover, in various murine pain models, licoisoflavone A showed a significant dose-dependent analgesic effect in reducing inflammatory and neuropathic pain, including those pain models induced by acetic acid, heat, complete Freund's adjuvant, and paclitaxel. Cell cytotoxicity assays, open-field tests, and rotarod tests confirmed licoisoflavone A exhibits a favorable safety profile. Our study uncovers the underlying mechanism of G. uralensis analgesia and suggests that licoisoflavone A is a promising candidate for targeting Na_V1.8 for pain therapy.