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Sources of Funding: These studies are supported by NIH /NIDDK R01 DK066112S1 (D.J. K.) and MAPP U01 DK82342 (D.J.K. and A.J.S.). _x000D_

Introduction

Chronic pelvic pain causes significant morbidity to patients and is a bane to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia BALB/c mice, relative to C57BL/6 mice. Here, we use a genetic strategy to identify a novel modulator of pelvic pain expressed along the bladder-brain axis._x000D_

Methods

Mouse SNP genotyping: We generated 96 F2 female mice, infected with PRV, and pelvic pain was scored in response to von Frey filament stimulus. Purified F2 mouse tail DNA was genotyped with Illumina Mouse MD arrays containing 1449 SNPs. We mapped QTL using R/qtl software. Knockout mice were evaluated for pelvic allodynia, and expression was localized by immunofluorescence._x000D_

Results

female F1CxB mice exhibit the low-allodynia phenotype of C57BL/6 parental mice in response to PRV, indicating that the severe pelvic pain phenotype of BALB/c mice is recessive. To identify loci modulating pelvic pain, we performed a quantitative trait locus (QTL) analysis on female F2CxB progeny by quantifying PRV-induced allodynia and statistical associations between pelvic pain and recombinant genotypes. Analyses identified a polymorphism on chromosome 13, rs6314295, significantly associated with allodynia (LOD=3.11). Expression analyses revealed that the mouse gene for acyloxyacyl hydrolase (AOAH), encoded near this SNP, was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited pelvic hypersensitivity compared to wild-type (WT) mice and developed extreme pelvic allodynia both in neurogenic and bacterial cystitis models. AOAH deficiency results in greater bladder pathology in neurogenic cystitis consistent with increased bladder mast cell activation. AOAH expression was detected along the bladder-brain axis, and AOAH-deficient mice have elevated levels of bladder VEGF, a UCPPS biomarker.

Conclusions

These findings indicate that AOAH is expressed along the bladder-brain axis and modulates pelvic pain severity and UCPPS biomarker expression. Thus, allelic variation in Aoah may mediate susceptibility to UCPPS symptoms.

Funding

These studies are supported by NIH /NIDDK R01 DK066112S1 (D.J. K.) and MAPP U01 DK82342 (D.J.K. and A.J.S.). _x000D_