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.

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.

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.

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.

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.

International journal of urology : official journal of the Japanese Urological Association. 2018 Aug 15 [Epub ahead of print]

Fei Ma, David E Hunt, Lin Leng, Richard Bucala, Katherine L Meyer-Siegler, Pedro L Vera

Research and Development, Lexington Veterans Affairs Medical Center, Lexington, Kentucky, USA., Department of Internal Medicine, Yale University, New Haven, Connecticut, USA., Department of Natural Sciences, St. Petersburg College, St. Petersburg, Florida, USA.