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.
Highlights
Bladder pain of unknown etiology has been associated with co-morbid conditions and functional abnormalities in neighboring pelvic organs
Absence of transient receptor potential vanilloid 1 (TRPV1) receptors does not eliminate the development of colonic inflammation Severity of inflammatory reaction induced by trinitrobenzene sulfonic acid (TNBS) in WT and TRPV1−/− mice was assessed by histological and biochemical methods as previously described [16,21]
Colonic inflammation up-regulates voltage-gated sodium channels in bladder sensory neurons from WT but not TRPV1−/− mice In the set of experiments we aimed to determine if knockdown of TRPV1 gene would affect excitability of bladder sensory neurons via effects on voltage-gated sodium channels (VGSC) as we previously reported for a rat model of cross-sensitization [16,31]
Summary
Bladder 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. The latest research efforts aimed at understanding the mechanisms underlying complex CPP disorders provided evidence that cross-sensitization in afferent pathways may initiate the development of neurogenic inflammation in the pelvis and functional chronic pelvic pain [7,8]. A pathological condition developed in one of the pelvic organs may cause initial sensitization of peripheral afferent fibers and sensory neurons. These primary changes lead to amplification of nociceptive signaling in the CNS followed by descending modulatory input from the CNS to the periphery [8,9,10]
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