Persistent inflammation results in an increase in the amplitude and duration of depolarization-evoked Ca²⁺transients in putative nociceptive afferents. Previous data indicated that these changes were the result of neither increased neuronal excitability nor an increase in the amplitude of depolarization. Subsequent data also ruled out an increase in voltage-gated Ca²⁺currents and recruitment of Ca²⁺-induced Ca²⁺release. Parametric studies indicated that the inflammation-induced increase in the duration of the evoked Ca²⁺transient required a relatively large and long-lasting increase in the concentration of intracellular Ca²⁺implicating the Na⁺/Ca²⁺exchanger (NCX), a major Ca²⁺extrusion mechanism activated with high intracellular Ca²⁺loads. The contribution of NCX to the inflammation-induced increase in the evoked Ca²⁺transient in rat sensory neurons was tested using fura-2 AM imaging and electrophysiological recordings. Changes in NCX expression and protein were assessed with real-time PCR and Western blot analysis, respectively. An inflammation-induced decrease in NCX activity was observed in a subpopulation of putative nociceptive neurons innervating the site of inflammation. The time course of the decrease in NCX activity paralleled that of the inflammation-induced changes in nociceptive behavior. The change in NCX3 in the cell body was associated with a decrease in NCX3 protein in the ganglia, an increase in the peripheral nerve (sciatic) yet no change in the central root. This single response to inflammation is associated with changes in at least three different segments of the primary afferent, all of which are likely to contribute to the dynamic response to persistent inflammation.