Ethnopharmacology relevance
Tripterygium wilfordii Hook. f. has been widely used in clinical practice due to its good anti-inflammatory and analgesic activities. However, its application is limited by potential toxicity and side effects.

Aim of the study
The study aimed to identify the mechanisms responsible for the pharmacological activity and cardiotoxicity of the main monomers of Tripterygium wilfordii.

Materials and methods
Database analysis predicted that ion channels may be potential targets of Tripterygium wilfordii. The regulatory effects of monomers (triptolide, celastrol, demethylzeylasteral, and wilforgine) on protein Nav1.5 and Nav1.7 were predicted and detected by Autodock and patch clamping. Then, we used the formalin-induced pain model and evaluated heart rate and myocardial zymograms to investigate the analgesic activity and cardiotoxicity of each monomer in vivo.

Results
All four monomers were able to bind to Nav1.7 and Nav1.5 with different binding energies and subsequently inhibited the peak currents of both Nav1.7 and Nav1.5. The monomers all exhibited analgesic effects on formalin-induced pain; therefore, we hypothesized that Nav1.7 is one of the key analgesic targets. Demethylzeylasteral reduced heart rate and increased the level of creatine kinase-MB, thus suggesting a potential cardiac risk; data suggested that the inhibitory effect on Nav1.5 might be an important factor underlying its cardiotoxicity.

Conclusion
Our findings provide an important theoretical basis for the further screening of active monomers with higher levels of activity and lower levels of toxicity.

Corydalis yanhusuo W. T. Wang, a traditional Chinese herbal medicine, has been used as an analgesic for thousands of years and it also promotes blood circulation. In this study, 33 Corydalis yanhusuo alkaloid active components were acquired from Traditional Chinese Medicine Database and Analysis Platform (TCMSP). A total of 543 pain-related targets, 1774 arrhythmia targets, and 642 potential targets of these active components were obtained using Swiss Target Prediction, GeneCards, Open Target Platform, and Therapeutic Target Database. Fifty intersecting targets were visualized through a Venn diagram, KEGG and GO pathway enrichment analysis. The analysis proposed that sodium ion channels are likely potential targets of Corydalis yanhusuo active components as analgesia and anti-arrhythmia agents. Molecular docking showed that the 33 components could bind to NaV1.7 and NaV1.5 (two subtypes of ion channel proteins) with different binding energies. In a patch clamp study, dihydrosanguinarine and dihydrochelerythrine, two monomers with the strongest binding effects, could inhibit the peak currents and promote both activation and inactivation phases of NaV1.5. Meanwhile, dihydrosanguinarine and dihydrochelerythrine could also inhibit peak currents and promote the activation phase of NaV1.7. Therefore, the findings from this study provide valuable information for future uses of traditional Chinese medicines to treat pain and cardiovascular disease.

Ethnopharmacology relevance - Pain is an unpleasant sensory and emotional experience, often accompanied by the occurrence of a variety of diseases. More than 800 kinds of traditional Chinese medicines (TCM) has now been reported for pain relief and several monomers have been developed into novel analgesic drugs. Bupleurum chinense and Angelica biserrata were representatives of the TCM that are currently available for the treatment of pain.

Existing methods to stimulate neural activity include electrical optical and chemical techniques. They have enabled the development of novel therapies that are used in clinical settings, in addition to helping understand aspects of neural function and disease mechanisms. Despite their beneficial impact, these approaches are fundamentally limited. Electrical stimulation is invasive, requiring direct contact with the target of interest. Inserting electrodes into the brain may lead to inflammation, bleeding, cell death, and local cytokine concentration increases in microglia that precipitate astrocyte formation around the electrodes that, in turn, reduce long-term effectiveness. In addition, it may have non-specific effects depending on the electric field generated by the electrodes and the stimulation parameters used. Transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (tMS) are new and non-invasive, yet they have poor spatial resolution on the order of 1 cm. Furthermore, approaches combining genetic tools with light or small molecules achieve cellular specificity. Optogenetics, which involves the use of light and genetically encoded membrane proteins, has enabled elucidation of cellular circuits in animal models. However, it remains an invasive technique and applications are limited by the depth of penetration of light in tissue. In contrast, chemogenetics, using small molecule sensitive designer receptors, is limited by poor temporal resolution and is unfortunately impractical for many neural applications that require millisecond response times