Abstract
BackgroundMast cells trigger inflammation that is associated with local pain, but the mechanisms mediating pain are unclear. Interstitial cystitis (IC) is a bladder disease that causes debilitating pelvic pain of unknown origin and without consistent inflammation, but IC symptoms correlate with elevated bladder lamina propria mast cell counts. We hypothesized that mast cells mediate pelvic pain directly and examined pain behavior using a murine model that recapitulates key aspects of IC.Methods and FindingsInfection of mice with pseudorabies virus (PRV) induces a neurogenic cystitis associated with lamina propria mast cell accumulation dependent upon tumor necrosis factor alpha (TNF), TNF-mediated bladder barrier dysfunction, and pelvic pain behavior, but the molecular basis for pelvic pain is unknown. In this study, both PRV-induced pelvic pain and bladder pathophysiology were abrogated in mast cell-deficient mice but were restored by reconstitution with wild type bone marrow. Pelvic pain developed normally in TNF- and TNF receptor-deficient mice, while bladder pathophysiology was abrogated. Conversely, genetic or pharmacologic disruption of histamine receptor H1R or H2R attenuated pelvic pain without altering pathophysiology.ConclusionsThese data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and TNF, respectively. Therefore, pain is independent of pathology and inflammation, and histamine receptors represent direct therapeutic targets for pain in IC and other chronic pain conditions.
Highlights
Interstitial cystitis (IC) is a chronic bladder inflammatory disease with unknown etiology that afflicts as many as 1 million patients in the United States
These data demonstrate that mast cells promote cystitis pain and bladder pathophysiology through the separable actions of histamine and tumor necrosis factor alpha (TNF), respectively
Since we previously showed that mast cells mediate the bladder pathophysiology of murine pseudorabies virus (PRV) cystitis, we hypothesized that pelvic pain is mediated by mast cells
Summary
IC is a chronic bladder inflammatory disease with unknown etiology that afflicts as many as 1 million patients in the United States. Mast cells contain preformed stores of immune mediators, such as histamine and TNF, and can be activated to release these stores by neurotransmitters such as substance P These observations have suggested a central role for mast cells in IC pathogenesis whereby activation of bladder-associated circuits in the central nervous system (CNS) initiates substance P release by peripheral nerves in the bladder that promotes substance P-mediated mast cell activation [6]. This mast cell activation, in turn, is postulated to induce bladder inflammation by acting on urothelium, the epithelium that lines the bladder.
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