AbstractThe transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1^−/− mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1^−/− mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP) and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP.