Capsaicin is a specific agonist of transient receptor potential vanilloid 1 (TRPV1), which is enriched in nociceptors.
Capsaicin not only produces
acute pain but also leads to long-lasting
analgesia in patients with
chronic pain. Although
capsaicin-induced TRPV1 and Ca 2+ /
calpain-dependent ablation of axonal terminals is necessary for long-lasting
analgesia, the mechanisms underlying
capsaicin-induced ablation of axonal terminals and its association with
analgesia are not fully understood. Microtubules are composed of
tubulin polymers and serve as a main axonal cytoskeleton maintaining axonal integrity. In this study, we hypothesized that
capsaicin would increase the depolymerization of microtubules and lead to axonal ablation and
analgesia for trigeminal
neuropathic pain.
Paclitaxel, a microtubule stabilizer, decreased
capsaicin-induced ablation of axonal terminals in time-lapsed imaging in vitro.
Capsaicin increases free
tubulin in dissociated sensory neurons, which was inhibited by
paclitaxel. Consistently,
subcutaneous injection of
paclitaxel prevented
capsaicin-induced axonal ablation in the hind paw skin.
Capsaicin administration to the facial skin produced
analgesia for
mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve, which was prevented by the coadministration of
paclitaxel and
capsaicin. Whole-mount staining of facial skin showed that
paclitaxel reduced
capsaicin-induced ablation of peptidergic afferent terminals. Despite the suggested involvement of TRPV1 Ser801 phosphorylation on microtubule integrity,
capsaicin-induced
analgesia was not affected in TRPV1 S801A knock-in mice. In conclusion,
capsaicin-induced depolymerization of axonal microtubules determined
capsaicin-induced ablation of nociceptive terminals and the extent of
analgesia. Further understanding of TRPV1/Ca 2+ -dependent mechanisms of
capsaicin-induced ablation and
analgesia may help to improve the management of chronic
pain.