Orofacial pain affects a significant portion of society both in terms of suffering and costs; however, effective therapies still remain elusive. Resiniferatoxin (RTX) is a vanilloid agonist that binds to the transient receptor potential channel, vanilloid subfamily member 1 (TRPV1). There is a great deal of evidence supporting a role for TRPV1 in modulating noxious-mediated and hyperalgesic responses. We hypothesized that targeting the trigeminal sensory nucleus region with RTX would provide long lasting analgesia for the orofacial region. We used operant and reflex behavioral measures and histological techniques to evaluate the effects of RTX on orofacial pain. Animals (n=8/group) were trained to complete a reward-conflict operant test at 48C. RTX (250ng) or vehicle was delivered intracisternally and animals were retested at 48C following carrageenan or capsaicin application to the facial region. There was a statistically significant decrease in operant and reflex measures for RTX-treated animals, indicating analgesia, as compared to baseline and vehicle control values following nociceptive activation. We observed a significant ablation of TRPV1-positive fibers within nucleus caudalis and reduction of inflammation-induced c-Fos-like immunoreactivity in animals treated with RTX. These data demonstrate that elimination of TRPV1-positive fibers using this approach may provide a viable treatment option for patients suffering severe pain from orofacial pain disorders/conditions/problems.