Dental injuries have been shown to generate extensive structural and cytochemical changes in sensory fibers that contain neuropeptides such as calcitonin gene-related peptide (CGRP) or substance P (SP). The present study was designed to test whether the anti-inflammatory drug dexamethasone (DEX) can alter neural responses to dental injuries. DEX (20 micrograms/100 g body weight) was given to adult rats (n = 10) prior to dental surgery and daily thereafter for 4 days. Control animals received sterile saline vehicle (n = 6) or no injection (n = 1). Each rat was then anesthetized for dental surgery and a cavity was drilled partway through dentin on the anterior side of the right maxillary first molar. Pulp exposure injuries were also made on two right mandibular molars in 14 of 17 rats. After 4 days of daily drug treatment, the rats were anesthetized and fixed by perfusion with formaldehyde-picric acid, and their jaws were prepared for immunocytochemistry. Neural CGRP immunoreactivity near the maxillary cavity injury site of DEX-treated rats was reduced more than 50% compared to controls, as determined both qualitatively and by digital analysis. The SP immunoreactive (IR) fibers in molar pulp also had extensive inhibition of neural reactions to cavity injury. DEX also reduced the immunoreactivity for CGRP and SP in normal contralateral rat molars of all treated rats, and it caused a postoperative loss of weight. Pretreatment for 1-5 days prior to the 4 day injury gave the same results as pretreatment for 1 h. The mandibular pulp exposure injuries induced a chronic abscess and advancing pulpal necrosis but did not show differences in nerve reactions between DEX-treated rats and the controls. In conclusion, the synthetic steroid dexamethasone suppressed the CGRP and SP neuropeptide immunoreactivity in normal dental nerves and it reduced nerve-sprouting responses to dentin cavity injuries; however, sensory nerve reactions to pulpal exposure injuries were not affected by DEX in these experiments.