Dexamethasone causes extensive physiologic reactions including the reduction of inflammation and pain. Here, we asked whether it also affected dental or periodontal cells or dental innervation by altering voltage-gated sodium channel Na(v)1.6 immunoreactivity (IR) or neural synaptophysin. Daily dexamethasone (0.2 mg/kg) given for 1 week to rats caused 12-fold increased intensity of Na(v)1.6-IR in dendritic pulpal cells of normal molars and incisors compared with vehicle treatment. These cells also co-localized monocyte (ED-1) or dendritic cell (CD11b/Ox42) markers, and their location in molars expanded during dexamethasone treatment to include deeper pulp. Furthermore, dexamethasone caused a 10-fold decrease in the number of Na(v)1.6-immunoreactive multinucleate osteoclasts along the alveolar bone of molar root sockets. No changes occurred for neural Na(v)1.6 at axonal nodes of Ranvier, even though IR for calcitonin gene-related peptide was greatly decreased, as expected, and neural synaptophysin-IR was decreased 59% by dexamethasone. At 4 days after tooth injury, pulpal vasodilation and increased Na(v)1.6-immunoreactive pulp cells were similar for all groups. Thus, dexamethasone changes dental pulp cell and alveolar osteoclast Na(v)1.6-IR in normal teeth, but different mechanisms occur after tooth injury when tissue reactions were similar for dexamethasone- and vehicle-treated rats. Steroid-induced alterations of dental pain and inflammation coincide with altered exocytic capability in dental nerve fibers as shown by synaptophysin-IR and with altered pulp cell Na(v)1.6-IR and osteoclast number, but not with any changes in Na(v)1.6-IR for nodes of Ranvier in myelinated dental axons.