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

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.

To determine whether ZOL modulates TRPV1 channel function and to elucidate the mechanism underlying its analgesic effects.

We combined behavioral assays of thermal nociception in mice and Drosophila melanogaster, Ca²⁺ imaging in primary dorsal root ganglion neurons, electrophysiological recordings from TRPV1 expressed in Xenopus laevis oocytes, and acute hippocampal slice recordings to assess TRPV1-dependent synaptic plasticity.

Systemic ZOL administration significantly reduced thermal nociceptive behaviors in both models without affecting locomotion or core temperature. In vitro, ZOL decreased capsaicin-evoked Ca²⁺ responses in dorsal root ganglion neurons and markedly reduced TRPV1-mediated currents in excised membrane patches from oocytes. In hippocampal slices, ZOL prevented TRPV1-dependent synaptic depression without altering basal transmission. Loss of inhibition under asymmetric ionic strength conditions suggests a pore-blocking mechanism.

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.