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Updated: Jun 7, 2025
Urinary Bladder Distention Evoked Visceromotor Responses as a Model for Bladder Pain in Mice
Published on: April 27, 2014
Modulation of persistent bladder pain in mice: The role of macrophage migration inhibitory factor, high mobility
Shaojing Ye1, Fei Ma1, Dlovan F D Mahmood1
1Lexington VA Health Care System, Research and Development, Lexington, KY, USA.
Background:
Repeated intravesical activation of protease-activated receptor-4 (PAR4) serves as a model of persistent bladder hyperalgesia (BHA) in mice, which lasts several days after the final stimulus. Spinal macrophage migration inhibitory factor (MIF) and high mobility group box 1 (HMGB1) are critical mediators in the persistence of BHA.
Objective:
We aimed to identify effective systemic treatments for persistent BHA using antagonists or transgenic deletions.
Methods:
Persistent BHA was induced through transurethral instillations of a PAR4-activating peptide (PAR4-AP; 100 μM, 1 h; scrambled peptide, control) under anesthesia, administered on Days 0, 2, and 4. Lower abdominal hypersensitivity was measured on Days 0-4 and 7-9. Systemic injections from Days 2-8 included ISO-1 (a MIF antagonist), ethyl pyruvate (an inhibitor of HMGB1 release), phosphate-buffered saline, or 10% DMSO (vehicle control) in C57BL/6 mice. To examine the role of HMGB1 receptors, Toll-like receptor-4 (TLR4)-null mice or systemic treatment with FPS-ZM1 (receptor for advanced glycation end product [RAGE] antagonist) were used. In addition, TIR-domain-containing adaptor-inducing interferon-β (TRIF)-null mice were tested to assess the involvement of TLR4 signaling pathways. Micturition volume and frequency were assessed on Day 9, and the bladder was histopathologically examined to assess inflammation and edema.
Results:
MIF antagonism significantly reversed persistent BHA, whereas HMGB1 antagonism led to a partial reduction of persistent BHA. TLR4 deficiency or systemic administration of FPS-ZM1 significantly mitigated persistent BHA, while TRIF-deficient mice experienced a faster onset of BHA. Only MIF or HMGB1 inhibition resulted in increased micturition volume. The histopathological examination revealed no changes in inflammation or edema.
Conclusion:
MIF and HMGB1, acting through TLR4 and RAGE, mediated persistent BHA, while TRIF might modulate its onset. Further exploration of downstream TLR4 signaling may uncover novel therapeutic targets for treating persistent bladder pain.
Insights
Systemic inhibition of macrophage migration inhibitory factor (MIF) and high mobility group box 1 (HMGB1) effectively treats persistent bladder hyperalgesia (BHA). These mediators, acting via Toll-like receptor-4 (TLR4) and receptor for advanced glycation end products (RAGE), are key to bladder pain persistence.
Area of Science:
- Urology
- Neuroscience
- Immunology
Background:
- Protease-activated receptor-4 (PAR4) activation models persistent bladder hyperalgesia (BHA) in mice.
- Spinal macrophage migration inhibitory factor (MIF) and high mobility group box 1 (HMGB1) are crucial for BHA persistence.
Purpose of the Study:
- To evaluate systemic treatments for persistent BHA.
- To investigate the role of MIF and HMGB1 antagonists and receptor pathways in BHA.
Main Methods:
- Persistent BHA induced by intravesical PAR4-activating peptide in mice.
- Systemic administration of MIF antagonist (ISO-1) and HMGB1 inhibitor (ethyl pyruvate).
- Assessment using Toll-like receptor-4 (TLR4)-null, TRIF-null, and RAGE antagonist (FPS-ZM1) models.
Main Results:
- MIF antagonism significantly reversed persistent BHA; HMGB1 antagonism partially reduced it.
- TLR4 deficiency and RAGE antagonism mitigated BHA; TRIF deficiency accelerated onset.
- MIF or HMGB1 inhibition increased micturition volume without affecting bladder inflammation.
Conclusions:
- MIF and HMGB1, via TLR4 and RAGE, mediate persistent BHA.
- TRIF may modulate BHA onset.
- Targeting downstream TLR4 signaling offers potential therapeutic strategies for bladder pain.
