Plant-Derived Secondary Metabolites Tetrahydropalmatine and Rutaecarpine Alleviate Paclitaxel-Induced Neuropathic Pain via TRPV1 and TRPM8 Modulation

BACKGROUND: (ER), as well as their major alkaloids tetrahydropalmatine (THP) and rutaecarpine, in a mouse model of paclitaxel-induced neuropathic pain. METHODS: Neuropathic pain was induced by paclitaxel administration (2 mg/kg, i.p., four injections). CY and ER extracts were orally administered at doses of 100 or 300 mg/kg, either alone or in combination, and cold and mechanical allodynia were assessed from days 0 to 8. The analgesic effects of THP and rutaecarpine were also examined. Gene and protein expression analyses were performed to evaluate the involvement of TRPV1 and TRPM8 signaling pathways, and high-performance liquid chromatography (HPLC) was used to confirm the presence of THP in CY and rutaecarpine in ER. RESULTS: Paclitaxel reliably induced robust cold and mechanical hypersensitivity. Oral administration of CY or ER significantly alleviated allodynia in a dose-dependent manner, with greater efficacy at 300 mg/kg. Combined CY-ER treatment produced stronger anti-allodynic effects than either extract alone. THP and rutaecarpine also exhibited dose-dependent analgesic effects, and their co-administration yielded the most pronounced inhibition of paclitaxel-evoked hypersensitivity. Molecular analyses confirmed the involvement of TRPV1- and TRPM8-related pathways in these analgesic effects. Collectively, these findings indicate that CY, ER, and their representative alkaloids effectively attenuate paclitaxel-induced neuropathic pain and highlight CY-ER-based natural products as promising candidates for managing CIPN through modulation of TRPV1/TRPM8 signaling.