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Differential effects of intravesical resiniferatoxin on excitability of bladder spinal neurons upon colon-bladder cross-sensitization.

ABSTRACT: Cross-sensitization in the pelvis may contribute to etiology of functional pelvic pain disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Increasing evidence suggests the involvement of transient receptor potential vanilloid 1 (TRPV1) receptors in the development of neurogenic inflammation in the pelvis and pelvic organ cross-sensitization. The objective of this study was to test the hypothesis that desensitization of TRPV1 receptors in the urinary bladder can minimize the effects of cross-sensitization induced by experimental colitis on excitability of bladder spinal neurons. Extracellular activity of bladder neurons was recorded in response to graded urinary bladder distension (UBD) in rats pretreated with intravesical resiniferatoxin (RTX, 10(-7)M). Colonic inflammation was induced by intracolonic instillation of 2,4,6-trinitrobenzene sulfonic acid (TNBS). The duration of excitatory responses to noxious UBD during acute colonic inflammation (3 days post-TNBS) was significantly shortened in the group with RTX pretreatment (25.3±1.5s, n=49) when compared to the control group (35.1±4.2s, n=43, p<0.05). The duration of long-lasting excitatory responses, but not short-lasting responses of bladder spinal neurons during acute colitis was significantly reduced by RTX from 52.9±6.6s (n=21, vehicle group) to 34.4±2.1s (RTX group, n=21, p<0.05). However, activation of TRPV1 receptors in the urinary bladder prior to acute colitis increased the number of bladder neurons receiving input from large somatic fields from 22.7% to 58.2% (p<0.01). The results of our study provide evidence that intravesical RTX reduces the effects of viscerovisceral cross-talk induced by colonic inflammation on bladder spinal neurons. However, RTX enhances the responses of bladder neurons to somatic stimulation, thereby limiting its therapeutic potential.

SUBMITTER: Malykhina AP

PROVIDER: S-EPMC3607291 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Differential effects of intravesical resiniferatoxin on excitability of bladder spinal neurons upon colon-bladder cross-sensitization.

Malykhina Anna P AP Qin Chao C Lei Qi Q Pan Xiao-Qing XQ Greenwood-Van Meerveld Beverley B Foreman Robert D RD

Brain research 20121109

Cross-sensitization in the pelvis may contribute to etiology of functional pelvic pain disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). Increasing evidence suggests the involvement of transient receptor potential vanilloid 1 (TRPV1) receptors in the development of neurogenic inflammation in the pelvis and pelvic organ cross-sensitization. The objective of this study was to test the hypothesis that desensitization of TRPV1 receptors in the urinary bladder can minimize the e ...[more]

PMID: 23146715

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Project description:BackgroundIrritable bowel syndrome and bladder pain syndrome often overlap and are both characterized by visceral hypersensitivity. Since pelvic organs share common sensory pathways, it is likely that those syndromes involve a cross-sensitization of the bladder and the colon. The precise pathophysiology remains poorly understood.AimTo develop a model of chronic bladder-colon cross-sensitization and to investigate the mech-anisms involved.MethodsChronic cross-organ visceral sensitization was obtained in C57BL/6 mice using ultrasound-guided intravesical injections of acetic acid under brief isoflurane anesthesia. Colorectal sensitivity was assessed in conscious mice by measuring intracolonic pressure during isobaric colorectal distensions. Myeloperoxidase, used as a marker of colorectal inflammation, was measured in the colon, and colorectal permeability was measured using chambers. c-Fos protein expression, used as a marker of neuronal activation, was assessed in the spinal cord (L6-S1 level) using immunohistochemistry. Green fluorescent protein on the fractalkine receptor-positive mice were used to identify and count microglia cells in the L6-S1 dorsal horn of the spinal cord. The expression of NK1 receptors and MAPK-p38 were quantified in the spinal cord using western blot.ResultsVisceral hypersensitivity to colorectal distension was observed after the intravesical injection of acetic acid vs saline (P < 0.0001). This effect started 1 h post-injection and lasted up to 7 d post-injection. No increased permeability or inflammation was shown in the bladder or colon 7 d post-injection. Visceral hypersensitivity was associated with the increased expression of c-Fos protein in the spinal cord (P < 0.0001). In green fluorescent protein on the fractalkine receptor-positive mice, intravesical acetic acid injection resulted in an increased number of microglia cells in the L6-S1 dorsal horn of the spinal cord (P < 0.0001). NK1 receptor and MAPK-p38 levels were increased in the spinal cord up to 7 d after injection (P = 0.007 and 0.023 respectively). Colorectal sensitization was prevented by intrathecal or intracerebroventricular injections of minocycline, a microglia inhibitor, by intracerebroventricular injection of CP-99994 dihydrochloride, a NK1 antagonist, and by intracerebroventricular injection of SB203580, a MAPK-p38 inhibitor.ConclusionWe describe a new model of cross-organ visceral sensitization between the bladder and the colon in mice. Intravesical injections of acetic acid induced a long-lasting colorectal hypersensitivity to distension, mediated by neuroglial interactions, MAPK-p38 phosphorylation and the NK1 receptor.

Project description:Background: Clinical investigation indicates a high level of co-morbidity between bladder overactivity and irritable bowel syndrome. The cross-sensitization of afferent pathways has been demonstrated to be the main reason for the cross-organ sensitization, but the underlying mechanism is unclear. Methods: A single dose of 2, 4, 6-trinitrobenzene sulfonic acid (TNBS) was applied to induce the colitis rat models by intracolonic administration. All rats were randomly divided into three groups: control, TNBS-3-day, and TNBS-7-day groups. Western blot and immunofluorescent staining were performed to detect the expression of the P2X3 receptor. The spontaneous contractions of the detrusor strip were measured to evaluate the detrusor contractility function. The micturition function was measured by a cystometry experiment. The intercontractile interval (ICI) and maximum bladder pressure (BP) were recorded. Results: The distal colon from colitis showed serious tissue damage or chronic inflammation after TNBS instillation (p < 0.01). However, there were no detectable histological changes in bladder among groups (p > 0.05). TNBS-induced colitis significantly increased P2X3 receptor expression on the myenteric and submucosal plexus of the distal colon and urothelium of the bladder, especially at day 3 post-TNBS (p < 0.05). Meanwhile, the expression of the P2X3 receptor on DRG neurons was increased in TNBS-induced colitis (p < 0.01). The detrusor strip of rats exhibited detrusor overactivity after days 3 and 7 of TNBS administration (p < 0.01), but inhibition of the P2X3 receptor had no effect (p > 0.05). Moreover, the rats with colitis exhibited the micturition pattern of bladder overactivity, manifested by decreased ICI and increased maximum BP (p < 0.05). Interestingly, inhibition of the P2X3 receptor by intrathecal injection of A-317491 alleviated bladder overactivity evoked by TNBS-induced colitis (p < 0.05). Conclusion: The upregulation of the P2X3 receptor in an afferent pathway involved in bladder overactivity evoked by TNBS-induced colonic inflammation, suggesting that the P2X3 receptor antagonist may be an available and novel strategy for the control of bladder overactivity.

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Differential effects of intravesical resiniferatoxin on excitability of bladder spinal neurons upon colon-bladder cross-sensitization.

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Differential effects of intravesical resiniferatoxin on excitability of bladder spinal neurons upon colon-bladder cross-sensitization.

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