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Kouzoukas DE, Ma F, Meyer-Siegler KL, Westlund KN, Hunt DE, Vera PL. Protease-Activated Receptor 4 Induces Bladder Pain through High Mobility Group Box-1. PLoS One. 2016 Mar 24;11(3):e0152055. doi: 10.1371/journal.pone.0152055. eCollection 2016.

Because pain is one of the defining symptoms of interstitial cystitis/painful bladder syndrome (IC/BPS), there is considerable interest in exploring new approaches to treatment that might directly act on key mechanisms of pain related to the disorder. Accordingly, investigators looked at activation of protease activated receptor 4 (PAR4) in the lining of the urinary tract (urothelium). In this article, the researchers note that PAR4 causes pain through release of urothelial macrophage migration inhibitory factor (MIF). In addition, a protein known as High Mobility Group Box-1 (HMGB1) has been shown to influence bladder pain in laboratory models of cystitis. Investigators ran a number of tests on female mice to explore the connection between PAR4 and these factors. Interestingly, they found that giving the mice glycyrrhizin, a substance that inhibits HMGB1, they were able to block abdominal hypersensitivity caused by activation of PAR4. Likewise, they were able to block release of HMGB1 by treating the mice with a substance that blocked MIF. These findings confirm that MIF and HMGB1 in the urothelium could be new targets for treatment in IC/BPS and other conditions associated with bladder pain.