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 Ca2+-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 TRPV1+ afferents in
neuropathic pain are 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 (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 TRPV1+ afferent terminals and that TRPV1+ afferents contribute to the maintenance of TNP.