Terahertz waves facilitate capsaicin expulsion from TRPV1

Transient receptor potential vanilloid 1 (TRPV1) is a critical non-selective cation channel involved in various biological and physiological processes, making it a promising drug target for treating multiple diseases. Capsaicin, a TRPV1 agonist, is widely used to relieve pain by desensitizing the TRPV1 with persistent stimulation. However, the initially intolerable burning sensation due to TRPV1 activation necessitates the use of antagonists to deactivate TRPV1 and mitigate discomfort, which yet causes thermoregulation disorders. In this study, molecular dynamics simulations reveal that frequency-specific terahertz (THz) waves can promote capsaicin unbinding from TRPV1, suggesting a spatiotemporally controlled approach for TRPV1 deactivation. The THz wave resonates with the hydroxyl group in the capsaicin head, increasing its rotational kinetic energy and promoting its rotation. This disrupts the key hydrogen bond between the hydroxyl group and TRPV1 residue E570, significantly reducing capsaicin's affinity for TRPV1. Our findings suggest that THz waves could mimic TRPV1 antagonists in a more flexible way, offering temporal control over capsaicin recruitment and expulsion (i.e., TRPV1 activation, desensitization, and deactivation) for more comfortable pain relief. In addition, this work enlightens a THz-based, pill-free strategy to control the pain induced by inflammatory ligands activated TRPV1.