# Trans-Chalcone alleviates overt pain-like behavior by targeting the activation of nociceptive neuron TRPV1 and TRPA1 channels

## TL;DR

Trans-Chalcone reduces pain-like behaviors by inhibiting the activation of TRPV1 and TRPA1 channels in nociceptive neurons.

## Contribution

This study is the first to show that Trans-Chalcone directly modulates nociceptive neuron TRPV1 and TRPA1 channels.

## Key findings

- TC inhibited acetic acid and PBQ-induced abdominal contortions by 58.8% and 54.6%, respectively.
- TC reduced capsaicin and AITC-induced paw flinching and licking by up to 52%.
- TC decreased calcium influx in dorsal root ganglia neurons stimulated by capsaicin and AITC.

## Abstract

Trans-Chalcone (TC) is an anti-inflammatory flavonoid that reduces hyperalgesia by targeting nuclear factor κB and inflammasome in gout arthritis model. However, a direct modulation of nociceptors by TC has never been investigated, which was the aim of the present study.

Experimental models of overt pain-like behaviors were applied as the stimuli-induced behavior depends, at least in part, on nociceptive neuron activation by the stimuli themselves making them suitable to investigate if a drug candidate can inhibit nociceptive neuron activation. The selected models involve transient receptor potential (TRP) vanilloid 1 (V1)+ and TRP ankyrin 1 (A1)+ nociceptive neuron activation.

TC (10 mg/kg, per oral, 30 min pretreatment) inhibited abdominal contortions induced by acetic acid (58.8%) and phenyl-p-benzoquinone (PBQ—54.6%), and paw flinching (44 and 48%) and licking (38 and 46%) triggered by formalin and complete Freund’s adjuvant (CFA—46 and 43%), indicating TC inhibits varied overt pain-like behaviors. Considering TRPV1 and TRPA1 channels are activated in those models, TC activity was also tested in experimental conditions in which capsaicin (a TRPV1 agonist)- and allyl isothiocyanate (AITC, a TRPA1 agonist)-triggered nociceptive behavior. TC inhibited capsaicin (44 and 37.5%) and AITC (35.1 and 52%) paw flinching and licking behavior. TC (3 μM) also reduced the calcium influx caused by capsaicin (30%) and AITC (37.6%) stimulation of primary dorsal root ganglia neurons. Additionally, TC inhibited CFA-induced hyperalgesia, paw inflammation without toxic effects.

TC reduces overt pain-like behavior, at least in part, by inhibiting nociceptive neuron TRPV1 and TRPA1 channels activation.

The online version contains supplementary material available at 10.1007/s10787-025-02099-w.