Protease activated-receptor 4 activation as a model of persistent bladder pain: Essential role of macrophage migration inhibitory factor and high mobility group box 1.

Abstract

OBJECTIVES:

To develop a rodent model of persistent non-inflammatory bladder pain and to test macrophage migration inhibitory factor and high mobility box group 1 as mediators of bladder pain.

METHODS:

Female C57BL/6 mice received intravesical instillations of protease activated receptor 4 (100 μmol/L, for 1 h) three times every other day and abdominal mechanical hypersensitivity (50% mechanical threshold) was tested on day 0 (baseline), and at days 1, 2, 3, 4, 7 and 9 after the first protease-activated receptor 4 injection. At the end of the experiment, micturition changes were measured and bladders were examined for histological changes. Macrophage migration inhibitory factor antagonist (MIF098; 40 mg/kg i.p. b.i.d.) or high mobility group box 1 inhibitor (glycyrrhizin; 50 mg/kg i.p. daily) was administered from day 2 until day 8.

RESULTS:

There was a significant and persistent decrease in abdominal mechanical threshold starting from day 3 in the protease-activated receptor 4-treated group that persisted until day 9 (5 days post-last instillation), but not in the control group. Glycyrrhizin fully reversed while MIF098 partially reversed abdominal mechanical hypersensitivity in protease-activated receptor 4-treated mice. The changes started on day 3 after the first protease-activated receptor 4 instillation, and analgesic effects lasted throughout the rest of the testing period. None of the groups had significant micturition changes or overt bladder histological changes.

CONCLUSIONS:

Repeated intravesical protease activated receptor 4 instillations produce persistent bladder pain without inflammation. Macrophage migration inhibitory factor and high mobility group box 1 are possible effective target molecules for bladder pain alleviation.

• Authors: Fei Ma, David E Hunt, Lin Leng, Richard Bucala, Katherine L Meyer-Siegler, Pedro L Vera
• Journal: International journal of urology : official journal of the Japanese Urological Association (Int J Urol) Vol. 25 Issue 10 Pg. 887-893 (10 2018) ISSN: 1442-2042 [Electronic] Australia
• PMID: 30112848 (Publication Type: Journal Article)
• Copyright: © 2018 The Japanese Urological Association.

Chemical References

• HMGB1 Protein
• HMGB1 protein, mouse
• Macrophage Migration-Inhibitory Factors
• Receptors, Thrombin
• Glycyrrhizic Acid
• Intramolecular Oxidoreductases
• Mif protein, mouse
• protease-activated receptor 4

Topics

• Administration, Intravesical
• Animals
• Disease Models, Animal
• Female
• Glycyrrhizic Acid (pharmacology, therapeutic use)
• HMGB1 Protein (antagonists & inhibitors, metabolism)
• Humans
• Intramolecular Oxidoreductases (antagonists & inhibitors, metabolism)
• Macrophage Migration-Inhibitory Factors (antagonists & inhibitors, metabolism)
• Mice
• Mice, Inbred C57BL
• Pelvic Pain (chemically induced, drug therapy, pathology)
• Receptors, Thrombin (administration & dosage)
• Urinary Bladder (drug effects, pathology)