<p>The electrical stimulation to gingiva induced the jaw-opening reflex (JOR). We have previously reported that the threshold for inducing jaw-opening reflex (JOR-TH) is significantly reduced by application of orthodontic force to teeth, and the intraperitoneal administration of TRPV1 antagonist recovers the JOR-TH. However, serious adverse side effects (e.g., hyperthermia) are reported by general administration of TRPV1 antagonists, and effective and safety application has to be established. In this study, TRPV1 and or TRPA1 antagonists were topically applied to gingiva, and the orthodontic force-induced JOR excitation was investigated with other features (e.g., trigeminal excitation, inflammatory cytokine alteration, rectal and gingival temperatures, and temperature sensitivity of the plantar and gingiva). Topical application of TRP antagonists immediately (D0)or one-day (D1)after orthodontic force application significantly increased JOR-TH the next day in dose-dependent and synergistic manner. On the other hand, there were no alterations in rectal and gingival temperature. In D0, the analgesic effect was associated with a significant reduction of CINC2 (cytokine-induced neutrophil chemoattractant-2) in the periodontium. In addition, chemical application-induced increase in temperature sensitivity was only observed in plantar. Taken together, topical application of TRP antagonists cocktail may reduce clinical orthodontic pain via CINC-2 reduction without adverse side effects.</p>