Activation of 5-HT_2A receptor by TCB2 improves bladder function in rats with bilateral pelvic nerve injury via TRPV4

Detrusor underactivity (DU) is a prevalent bladder dysfunction for which effective treatment is lacking. A series of studies have shown that the 5-HT_2A receptor is involved in the regulation of micturition, but its role in DU remains unknown. Besides, transient receptor potential vanilloid 4 (TRPV4) agonist has been demonstrated to improve bladder function in BPNI rats by increasing afferent signals and the 5-HT/5-HT_2A receptor are functionally associated with TRPV4 in several pathophysiological processes. In the current study, we established a bilateral pelvic nerve injury (BPNI) model. Tissue staining and cystometry were performed and the results showed that the BPNI model exhibited DU in both histological and urodynamic manifestations. Intrathecal injection of the 5-HT_2A receptor agonist TCB2 could facilitate the micturition reflex in BPNI rats, reducing intercontraction interval (ICI), residual volume (RV), and bladder capacity (BC), which could be reversed by the TRPV4 antagonist HC-067047. Western blot and immunofluorescence analyses revealed there was no significant difference in the expression of the 5-HT_2A receptor in the L6-S1 dorsal root ganglia (DRG) and spinal dorsal horn between sham-operated and BPNI rats, whereas the expression of TRPV4 was significantly decreased in BPNI rats. Calcium imaging of DRG neurons showed an increased calcium influx induced by TCB2, which was blocked by HC-067047. These findings suggest that the 5-HT_2A receptor agonist can improve bladder dysfunction in BPNI rats by regulating the micturition reflex via TRPV4. The 5-HT_2A receptor may be a potential therapeutic target for the treatment of DU.