Zoledronic acid produces analgesia by inhibiting the transient receptor potential vanilloid 1 (TRPV1) channel.

Introduction: The TRPV1 channel is activated by noxious heat and capsaicin and is expressed in primary nociceptive fibers, where it plays a key role in pain perception and inflammation. Although vanilloid compounds can induce topical analgesia, their systemic use is limited by thermoregulatory side effects. Zoledronic acid (ZOL), a bisphosphonate widely used to treat bone disorders and cancer-associated bone loss, has reported analgesic properties, although its effects on TRPV1 remain incompletely understood. Objective: To determine whether ZOL modulates TRPV1 channel function and to elucidate the mechanism underlying its analgesic effects. Methods: We combined behavioral assays of thermal nociception in mice and Results: Systemic ZOL administration significantly reduced thermal nociceptive behaviors in both models without affecting locomotion or core temperature. In vitro, ZOL decreased capsaicin-evoked Ca Conclusions: Our findings identify a previously unrecognized pore-blocking mechanism by which zoledronic acid inhibits TRPV1 channel activity, providing a mechanistic explanation for its analgesic effects. These results support a potential role for bisphosphonates as scaffolds for the development of novel analgesics and as tools to probe TRPV1-mediated pain pathways.