Lack of transient receptor potential vanilloid 1 channel modulates the development of neurogenic bladder dysfunction induced by cross-sensitization in afferent pathways

Abstract

BackgroundBladder pain of unknown etiology has been associated with co-morbid conditions and functional abnormalities in neighboring pelvic organs. Mechanisms underlying pain co-morbidities include cross-sensitization, which occurs predominantly via convergent neural pathways connecting distinct pelvic organs. Our previous results showed that colonic inflammation caused detrusor instability via activation of transient receptor potential vanilloid 1 (TRPV1) signaling pathways, therefore, we aimed to determine whether neurogenic bladder dysfunction can develop in the absence of TRPV1 receptors.MethodsAdult male C57BL/6 wild-type (WT) and TRPV1−/− (knockout) mice were used in this study. Colonic inflammation was induced by intracolonic trinitrobenzene sulfonic acid (TNBS). The effects of transient colitis on abdominal sensitivity and function of the urinary bladder were evaluated by cystometry, contractility and relaxation of detrusor smooth muscle (DSM) in vitro to various stimuli, gene and protein expression of voltage-gated sodium channels in bladder sensory neurons, and pelvic responses to mechanical stimulation.ResultsKnockout of TRPV1 gene did not eliminate the development of cross-sensitization between the colon and urinary bladder. However, TRPV1−/− mice had prolonged intermicturition interval and increased number of non-voiding contractions at baseline followed by reduced urodynamic responses during active colitis. Contractility of DSM was up-regulated in response to KCl in TRPV1−/− mice with inflamed colon. Application of Rho-kinase inhibitor caused relaxation of DSM in WT but not in TRPV1−/− mice during colonic inflammation. TRPV1−/− mice demonstrated blunted effects of TNBS-induced colitis on expression and function of voltage-gated sodium channels in bladder sensory neurons, and delayed development of abdominal hypersensitivity upon colon-bladder cross-talk in genetically modified animals.ConclusionsThe lack of TRPV1 receptors does not eliminate the development of cross-sensitization in the pelvis. However, the function of the urinary bladder significantly differs between WT and TRPV−/− mice especially upon development of colon-bladder cross-sensitization induced by transient colitis. Our results suggest that TRPV1 pathways may participate in the development of chronic pelvic pain co-morbidities in humans.

TRPV1 in experimental autoimmune prostatitis

“…Moreover, we observed abundant leukocyte infiltration in the stroma and near epithelial cells (red arrows) in the DLP lobes from B6 mice with EAP (Figure Ab). Interestingly, our TRPV1 KO mouse data were consistent with studies that suggest that the absence of the TRPV1 channel does not diminish tissue inflammation, since we observed that the DLP lobes from TRPV1 KO mice with EAP showed a significantly higher level of inflammation (69%) and leukocyte infiltration (red arrow) compared to respective controls (Figure Ca,b and D). In addition, we confirmed that the ventral (Figure Ac,d and Cc,d) and anterior (Figure Ae,f and Ce,f) prostates lobes obtained from B6 and TRPV1 KO mice with EAP do not show significant inflammation at day 20 (Figure B and D; respectively).…”

“…Prostate sections stained with H&E and scored for inflammation showed that B6 mice with EAP developed significantly higher levels of inflammation (72%) in the DLP lobes Moreover, we observed abundant leukocyte infiltration in the stroma and near epithelial cells (red arrows) in the DLP lobes from B6 mice with EAP ( Figure 2Ab). Interestingly, our TRPV1 KO mouse data were consistent with studies that suggest that the absence of the TRPV1 channel does not diminish tissue inflammation, [41][42][43] since we observed that the DLP lobes from TRPV1 KO mice with EAP showed a significantly higher level of inflammation (69%) and leukocyte infiltration (red arrow) compared to respective controls (Figure 2Ca,b and 2D). In addition, we confirmed that the ventral (Figure 2Ac Since inflammation was predominantly observed in the DLP lobes at day 20, we asked whether TRPV1 expression was altered in the DLP lobes from B6 mice with EAP.…”

Coronavirus-induced demyelination of neural pathways triggers neurogenic bladder overactivity in a mouse model of multiple sclerosis

“…Bladder catheter placement required animal anesthetization with isoflurane (VEDCO, St. Joseph, MO). Next, a PTF catheter with a blunted end (polyethylene-50, Clay Adams) was sutured in place at the bladder dome and tunneled out of the abdomen to the nape of the neck, where it was then inserted into the end of an angiocath catheter, as previously described (26). The angiocath was first tested with a gentle saline infusion to reveal no leak at the bladder and then anchored to the fascia and skin of the neck using two to three 5-0 Vicryl sutures.…”

Estrous Cycle Dependent Fluctuations of Regulatory Neuropeptides in the Lower Urinary Tract of Female Rats upon Colon-Bladder Cross-Sensitization

“…Recent clinical and translational studies provide evidence that co-occurrence of bladder, bowel and non-specific pelvic pain symptoms may be due to development of cross-sensitization in the pelvis via neural mechanisms [5]–[7] and on the possible modulation of such pain by sex hormones [8]. Our previous animal data from males established an association between inflammation in the pelvis, release of pro-inflammatory neuropeptides from pelvic afferents, and development of pelvic organ cross-sensitization [9], [10].…”