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The exchange of fluids and chemicals between the tooth pulp and the periphery, through the dentinal tubules has been well documented. Application of irritants on the open tubules produces aversion in awake rats that can be prevented by prior occlusion of these tubules. This study aims at characterizing the secretion of inflammatory mediators in tooth perfusates and assessing the effects of systemic pretreatment with anti-inflammatory drugs on the levels of these mediators. Several groups of rats (n = 5–6 each) were used for intradental application of either saline, capsaicin (100 μg in 100 μl), or endotoxin (20 μg in 100 μl) for a period of 40 min followed by filling the perfusion chamber with sterile saline and collecting the perfusate every 30 min for 6 h. The perfusates were used for the determination of the concentrations of cytokines by ELISA. Application of irritants produced a highly significant increase in PGE2 (peak at 2 h) and NGF (peak at 4–6 h). Dexamethasone antagonized the effects of endotoxin and capsaicin, while NSAID affected mainly the endotoxin-induced inflammation. Our results confirm the validity of the tooth perfusion technique and demonstrate that the efficacy of treatment with anti-inflammatory drugs depends on the type of inflammation.