Capsaicin-induced depolymerization of axonal microtubules mediates analgesia for trigeminal neuropathic pain

Abstract

Pain management in craniofacial neuropathy is a major clinical challenge. Trigeminal neuralgia and painful post-traumatic trigeminal neuropathy are two major trigeminal neuropathic pain that need to be addressed. Capsaicin a specific agonist of transient receptor potential vanilloid 1 (TRPV1), a Ca2+-permeable ion channel, that is enriched in nociceptors. The capacity of capsaicin to ablate TRPV1-expressing nociceptive terminals has led to an FDA-approved therapy treat neuropathic pain conditions. We showed that capsaicin induces ablation of nociceptive nerve terminals through TRPV1/Ca2+/calpain-mediated mechanisms, which is necessary for long-lasting analgesia for neuropathic pain. However, the mechanisms underlying capsaicin-induced ablation and analgesia to achieve pain control are not fully understood. In this study, we hypothesize that capsaicin increases depolymerization of microtubules, which induces axonal ablation and analgesia for trigeminal neuropathic pain. To test the hypothesis, we determined the effects of microtubule stabilizer; paclitaxel, which binds to microtubules and stabilizes microtubules against depolymerization, on capsaicin-induced axonal ablation and analgesia for trigeminal neuropathic pain in mice. Paclitaxel decreased capsaicin-induced ablation of axonal terminals in-vitro in time-lapse imaging of axonal terminals from microfluidic chamber. Capsaicin increases the proportion of free tubulin in dissociated sensory neurons, which was inhibited by paclitaxel treatment, suggesting capsaicin increases depolymerization of microtubules. Subcutaneous injection of capsaicin to facial skin attenuated mechanical allodynia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). In contrast, co-administration of paclitaxel and capsaicin did not produce analgesic effects. Results from the present study supports that TRPV1-microtubule interactions can determine capsaicin-induced ablation of nociceptive terminals and the extent of capsaicin-induced analgesia, which further supports that capsaicin-induced ablation of nociceptive terminals is necessary for analgesia. Further understanding of TRPV1/Ca2+-dependent mechanisms of capsaicin-induced ablation and analgesia may help to improve the efficacy of this treatment. Support/grant information: NIH R01 DE027731 and R35 DE030045 Support/grant information: NIH R01 DE027731 and R35 DE030045.