The Involvement of Endothelin Pathway in Chronic Psychological Stress-Induced Bladder Hyperalgesia Through Capsaicin-Sensitive C-Fiber Afferents

Introductions: Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood chronic disorder characterized by bladder related pain. Chronic psychological stress plays a key role in the exacerbation and development of IC/BPS via unclear mechanisms. This study aimed to investigate the role of endothelin 1 (ET-1) and its receptors in the development of chronic stress-induced bladder dysfunction. Methods: Wistar-Kyoto rats were exposed to chronic (10 days) water avoidance stress (WAS) or sham stress, with subgroups receiving capsaicin pretreatment to desensitize C-fiber afferents. Thereafter, cystometrograms (CMG) were obtained with visceromotor response (VMR) simultaneously during intravesical saline or ET-1 infusion. CMG recordings were analyzed for the first and the continuous voiding cycles, respectively. Endothelin receptor type A (ETAR) expression was examined in the bladder tissues and L6-S1 dorsal root ganglions (DRGs). Toluidine blue staining was to check the bladder inflammation and double-labeling immunofluorescence (IF) staining was to identify the locations of ETAR, respectively. Results: During saline infusion, WAS rats elicited significant decreases in pressure threshold (PT) and in the ratio of VMR threshold/ maximum intravesical pressure (IVPmax), and a significant increase in VMR duration and area under the curve (AUC). ET-1 infusion induced similar alternations in WAS rats, but further significantly diminished the pressure to trigger PT and VMR, together with a more forceful and longer VMR. The sole effect of WAS exposure or ET-1 administration on the micturition reflex could be suppressed by capsaicin pretreatment. WAS exposure significantly induced an increased number of total mast cells in the bladder, while capsaicin pretreatment possibly antagonized them. No significant difference in ETAR expression was found between all groups. IF staining indicated the co-localization of ETAR and calcitonin gene-related peptides in both bladder and DRGs. Conclusion: The activation of ET-1 receptors could enhance chronic stress-induced bladder hypersensitization and hyperalgesia through capsaicin-sensitive C-fiber afferents. Targeting the endothelin pathway may have therapeutic value for IC/BPS.