Papers of the Week

Trigeminal neuropathic pain (TNP) is often resistant to current pharmacotherapy and there is a pressing need to develop more efficacious treatments. Capsaicin is a pungent ingredient of chili peppers and specifically activates transient receptor potential vanilloid subtype 1 (TRPV1), a Ca-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the pre-existing pathological pain from the same region. However, the mechanisms underlying capsaicin-induced analgesia are not well understood. Although the reports of the involvement of TRPV1 and TRPV1+ afferents in neuropathic pain is controversial, we recently demonstrated that TRPV1 and TRPV1+ afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage afferents attenuated mechanical hyperalgesia and ongoing pain. In mice with ION-CCI, we found that a single focal injection of capsaicin into facial skin led to attenuation of mechanical hyperalgesia over two weeks. Capsaicin treatment also attenuated secondary hyperalgesia in extraterritorial mandibular skin. Furthermore, capsaicin treatment decreased ongoing pain. Longitudinal two-photon imaging of cutaneous nerve fibers showed that such capsaicin-induced analgesia is correlated with cutaneous nerve terminal density. Furthermore, preventing capsaicin-induced ablation of afferent terminals by co-administration of capsaicin with MDL28170, an inhibitor of calpain, abolished capsaicin-induced analgesia. These results suggest that a single focal injection of capsaicin induces long-lasting analgesia for neuropathic pain via selective ablation of TRPV1+ afferent terminals and that TRPV1+ afferents contribute to the maintenance of trigeminal neuropathic pain. Capsaicin has long been used as an analgesic to treat chronic pain conditions. Topical capsaicin is a FDA-approved treatment for neuropathic pain. However, the mechanisms underlying capsaicin-induced analgesia have been enigmatic for centuries. Despite evidence for clinical analgesia, data supporting the analgesic effects of capsaicin on neuropathic pain in preclinical model is rare. We found that a single focal injection of capsaicin to facial skin robustly attenuated trigeminal neuropathic pain in mice for longer than two weeks, which is mediated by localized ablation of TRPV1+ terminals in the skin. These results suggest that TRPV1+ afferents contribute to the maintenance of TNP and that capsaicin injection could be a safe and effective treatment for TNP.