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

## TL;DR

This study shows that plant compounds THP and rutaecarpine reduce neuropathic pain caused by paclitaxel by affecting TRPV1 and TRPM8 pathways.

## Contribution

The study identifies CY and ER alkaloids as novel natural agents for managing chemotherapy-induced neuropathy via TRP channel modulation.

## Key findings

- CY and ER extracts reduced cold and mechanical allodynia in a dose-dependent manner.
- THP and rutaecarpine together showed stronger analgesic effects than when used alone.
- TRPV1 and TRPM8 pathways were confirmed to be involved in the observed analgesic effects.

## Abstract

Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a major dose-limiting adverse effect of paclitaxel and is characterized by cold and mechanical allodynia. Effective therapeutic strategies for CIPN remain limited. This study evaluated the analgesic potential of Corydalis yanhusuo (CY) and Evodia rutaecarpa (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.