Background: Interstitial cystitis/painful bladder syndrome (IC/PBS), is a severely debilitating chronic condition that is frequently unresponsive to conventional pain medications. The etiology is unknown, however evidence suggests that nervous system sensitization contributes to enhanced pain in IC/PBS. In particular, central nervous system plasticity of glutamatergic signaling involving NMDA and metabotropic glutamate receptors (mGluRs) has been implicated in a variety of chronic pain conditions. Here, we test the hypothesis that mGluR5 mediates both non-inflammatory and inflammatory bladder pain or nociception in a mouse model by monitoring the visceromotor response (VMR) during graded bladder distention. Results: Using a combination of genetic and pharmacologic approaches, we provide evidence indicating that mGluR5 is necessary for the full expression of VMR in response to bladder distention in the absence of inflammation. Furthermore, we observed that mice infected with a uropathogenic strain of Escherichia coli (UPEC) develop inflammatory hyperalgesia to bladder distention, and that the selective mGluR5 antagonist fenobam [N-(3-chlorophenyl)-N′-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2-yl) urea], reduces the VMR to bladder distention in UPEC-infected mice. Conclusions: Taken together, these data suggest that mGluR5 modulates both inflammatory and non-inflammatory bladder nociception, and highlight the therapeutic potential for mGluR5 antagonists in the alleviation of bladder pain.

Purpose To characterize the urologic symptoms of a subset of urologic chronic pelvic pain syndrome (UCPPS) patients who have both a high somatic symptom burden and a wide symptom distribution fitting a “poly-symptomatic, poly-syndromic” (PSPS) pattern of presentation. Materials and Methods 81 UCPPS patients enrolled in the NIDDK MAPP Research Network Study at the Washington University in St. Louis and the University of Alabama at Birmingham sites completed a symptom questionnaire to assess their somatic symptom burden and its distribution, the Genitourinary Pain Index (GUPI) to assess their UCPPS symptoms and impact on quality of life, and self-reported treatment-seeking behaviors for their UCPPS symptoms. The PSPS symptom pattern was defined as self-report of numerous painful and non-painful somatic symptoms across many organ systems and symptom categories on the PSPS questionnaire. Results UCPPS patients with the PSPS pattern reported more severe genitourinary pain on a Likert scale, more frequent pain in the past week, and more widespread distribution of the pain in the genital and pelvic areas compared to UCPPS patients without PSPS. PSPS patients also had significantly higher scores on the pain subscale, quality of life subscale (worse), and the total scores on the GUPI questionnaire than patients without PSPS. Patients with the PSPS pattern reported significantly more treatment-seeking behaviors than other patients. Conclusion The PSPS pattern might be an important phenotypic factor to assess in the evaluation of UCPPS with clinical and research implications. This may be a distinct clinical subgroup among UCPPS patients.

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Gene expression changes are orchestrated by transcription factors (TFs), which bind to DNA to regulate gene expression. It remains surprisingly difficult to predict basic features of the transcriptional process, including in vivo TF occupancy. Existing thermodynamic models of TF function are often not concordant with experimental measurements, suggesting undiscovered biology. Here, we analyzed one of the most well-studied TFs, the yeast zinc cluster Gal4, constructed a Shea–Ackers thermodynamic model to describe its binding, and compared the results of this model to experimentally measured Gal4p binding in vivo. We found that at many promoters, the model predicted no Gal4p binding, yet substantial binding was observed. These outlier promoters lacked canonical binding motifs, and subsequent investigation revealed Gal4p binds unexpectedly to DNA sequences with high densities of its half site (CGG). We confirmed this novel mode of binding through multiple experimental and computational paradigms; we also found most other zinc cluster TFs we tested frequently utilize this binding mode, at 27% of their targets on average. Together, these results demonstrate a novel mode of binding where zinc clusters, the largest class of TFs in yeast, bind DNA sequences with high densities of half sites.

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