Anti‐nociceptive action of leonurine through TRPA1 and TRPV4 channels modulation

Background and Purpose: Leonurine, a pseudoalkaloid derived from Leonotis leonurus, has been traditionally used in herbal medicine to alleviate conditions such as headaches and abdominal discomfort. Its therapeutic effects are often attributed to potential antioxidant properties; however, the precise molecular mechanisms remain poorly understood. Transient Receptor Potential (TRP) channels, particularly TRPA1 and TRPV4, serve as critical sensors of reactive oxygen species (ROS). Persistent ROS elevation can contribute to pain by activating these channels. Experimental Approach: Here, we examined the antinociceptive properties of leonurine and its modulatory effects on TRPA1 and TRPV4 channels after stimulation with selective (allyl isothiocyanate (AITC) and GSK1016790A, respectively) or non-selective (hydrogen peroxide, H2O2) agonists. Employing human and murine cell lines expressing TRPA1 and TRPV4, and mouse primary sensory neurons from dorsal root ganglia (DRG), we observed that leonurine elicited a selective, concentration-dependent increase in intracellular calcium levels, followed by desensitisation of both channels. Notably, TRPA1 and TRPV4 have been implicated in the development and maintenance of mechanical allodynia within models of chemotherapy-induced peripheral neuropathy (CIPN). We used a thalidomide CIPN model to assess the efficacy of leonurine to reduce TRPA1- and TRPV4-dependent mechanical allodynia. Key Results: Our findings indicate that repeated, but not acute, administration of leonurine significantly reduced thalidomide-induced mechanical allodynia, highlighting the crucial role of TRPA1 and TRPV4 desensitisation in pain modulation. Conclusions and Implications: These results position leonurine as a promising candidate for pain management, warranting further investigation into long-term therapeutic strategies and potential clinical applications.