Up-regulation of phosphorylated CREB but not c-Jun in bladder afferent neurons in dorsal root ganglia after cystitis.

Abstract

We examined the changes of two transcription factors, CREB and c-Jun, in dorsal root ganglia (DRG) after acute (8 or 48 hours) or chronic (10 days) cyclophosphamide (CYP)-induced cystitis. Results showed an increase in the number of p-CREB-immunoreactive (-IR) cells in the L1 and L2 DRG (5-7-fold; P < or = 0.05) as well as L6 and S1 DRG (2-4-fold; P < or = 0.05) after acute and chronic cystitis. The number of p-CREB-IR cells in the L4-L5 DRG was not altered with cystitis. The number of c-Jun-IR cells increased in the L1-L2 DRG (L1: 10-fold; L2: 8-fold; P < or = 0.05) only with chronic cystitis, although it increased in the L6-S1 DRG with CYP-induced cystitis of acute (2-3-fold; P < or = 0.05) and chronic (6-10-fold; P < or = 0.05) duration. After CYP treatment, the percentage of bladder afferent cells expressing p-CREB immunoreactivity (3-7-fold; P < or = 0.05) increased in L1, L2, L6, and S1 DRG. The increase occurred 8 hours post-CYP injection and was maintained with chronic cystitis. There were few c-Jun-IR cells in the bladder afferent population. These results demonstrate that CYP induces p-CREB and c-Jun expression in DRG in a time-dependent manner. However, c-Jun expression is not associated with bladder afferent neurons. Resiniferatoxin reduced CYP-induced up-regulation of p-CREB in DRG, suggesting that cystitis can reveal an altered CREB phosphorylation that may be mediated by capsaicin-sensitive bladder afferents. Colocalization of p-CREB and Trk receptor(s) showed that a subpopulation of p-CREB-IR cells expressed p-Trk with cystitis. These results suggest that up-regulation of p-CREB may be mediated by a neurotrophin/Trk signaling pathway.