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The effects of corticosterone (CORT), a natural glucocorticoid hormone, on ATP-induced currents in rat dorsal root ganglion (DRG) neurons and the underlying signaling mechanism were studied by using patch-clamp techniques. Three types of currents (fast, slow and mixed) were evoked by ATP in cultured DRG neurons. Pretreatment with CORT (0.01–10 μmol/l) for 30 s could inhibit the fast current and the fast component of the mixed current. In contrast, CORT had no significant effect on the slow current evoked by ATP. The inhibitory effects were concentration dependent, reversible and could be blocked by glucocorticoid receptor antagonist RU38486 (10 μmol/l), but not by GDP-β-S (0.2 mmol/l), a blocker of G protein activation. Membrane-impermeable bovine serum albumin-conjugated corticosterone failed to mimic the effects of CORT. The inhibitory effects of CORT on ATP-induced currents diminished after adding protein kinase A inhibitor H89 (10 μmol/l), but were not influenced by protein kinase C inhibitor chelerythrine chloride (10 μmol/l). These results suggest that glucocorticoid hormones might participate in the control of pain by modulating P2X3 receptor-mediated events in sensory neurons, and the effect is mediated by glucocorticoid receptors and the downstream activation of protein kinase A. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]