Ablation of TRPV1+ Afferent Terminals by Capsaicin Mediates Long-Lasting Analgesia for Trigeminal Neuropathic Pain

Abstract

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 21-permeable ion channel. Topical capsaicin invariably induces burning pain. Paradoxically, the transient pain is often followed by prolonged attenuation of the preexisting pathologic 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 TRPV11 afferents in neuropathic pain are controversial, we recently demonstrated that TRPV1 and TRPV11 afferents are involved in mechanical hyperalgesia in mice with chronic constriction injury of the infraorbital nerve (ION-CCI). Consistently, chemogenetic inhibition of TRPV1-lineage (TRPV1-LN) 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 in vivo 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 TRPV11 afferent terminals and that TRPV11 afferents contribute to the maintenance of TNP.

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

“…1,3,11 Recent preclinical studies have established the causal contribution of capsaicin-induced ablation of afferent terminals to prolonged analgesia for trigeminal neuropathic pain. 42,43 In mice with chronic constriction injury of the infraorbital nerve (ION-CCI), a single subcutaneous injection of capsaicin to the face produces 2-week long analgesia for mechanical allodynia and ongoing pain. 43 Ca 21 -dependent protease calpain mediates capsaicin-induced ablation of TRPV1-expressing cutaneous afferents, and pharmacological inhibition of calpain prevents capsaicin-induced analgesia for neuropathic pain.…”

Injectable Capsaicin for the Management of Pain Due to Osteoarthritis

“…Leading candidates include mitochondrial mechanisms, and direct effects on microtubules linked specifically with TRPV1 [5]. Despite an incomplete understanding of the mechanisms, a recent preclinical study verified that disruption of TRPV1-expressing afferent terminals by capsaicin is necessary for long-lasting analgesia related to neuropathic pain [21]. The conclusion is that disruption of TRPV1-expressing terminals of nociceptive afferents likely underlies the long-term analgesia produced by capsaicin.…”

Acute and Chronic Pain from Facial Skin and Oral Mucosa: Unique Neurobiology and Challenging Treatment

“…The neurobiological mechanisms underlying trigeminal neuropathic pain have been determined using multiple preclinical rodent models. Most animal models of trigeminal neuropathic pain involve direct injury to the peripheral branches of trigeminal nerves, such as the infraorbital nerve [ 63 , 64 ], and mimic the characteristics of PTTN. A rat model with a compressed trigeminal nerve root mimics the painful conditions from TN: focal demyelination of the trigeminal nerve root, prolonged mechanical and cold allodynia, and the suppression of pain by carbamazepine [ 65 ].…”

“…Interestingly, CGRP receptor antagonists reduce the mechanical allodynia in rats with chronic constriction injury of the infraorbital nerve but not of the sciatic nerve [ 69 ], reflecting the differential contributions of neuropeptides to the maintenance of neuropathic pain in facial versus spinal areas. The role of primary afferents in the maintenance of trigeminal neuropathic pain has been further strengthened through studies of the long-lasting analgesia of localized capsaicin injection into the facial skin [ 63 ]. Nerve injury to the maxillary V2 nerves enhances the functions of primary afferent neurons not only in the V2 but also the V3 area ( Figure 5 A–D).…”