BackgroundVulvodynia is a remarkably prevalent chronic pain condition of unknown etiology. Epidemiologic studies associate the risk of vulvodynia with a history of atopic disease. We used an established model of hapten-driven contact hypersensitivity to investigate the underlying mechanisms of allergy-provoked prolonged sensitivity to pressure.MethodsWe sensitized female ND4 Swiss mice to the hapten oxazolone on their flanks, and subsequently challenged them four days later with oxazolone or vehicle for ten consecutive days on the labia. We evaluated labiar sensitivity to touch, local mast cell accumulation, and hyperinnervation after ten challenges.ResultsOxazolone-challenged mice developed significant tactile sensitivity that persisted for over three weeks after labiar allergen exposures ceased. Allergic sites were characterized by mast cell accumulation, sensory hyper-innervation and infiltration of regulatory CD4+CD25+FoxP3+ T cells as well as localized early increases in transcripts encoding Nerve Growth Factor and nerve-mast cell synapse marker Cell Adhesion Molecule 1. Local depletion of mast cells by intra-labiar administration of secretagogue compound 48/80 led to a reduction in both nerve density and tactile sensitivity.ConclusionsMast cells regulate allergy-provoked persistent sensitivity to touch. Mast cell-targeted therapeutic strategies may provide novel means to manage and limit chronic pain conditions associated with atopic disease.

Vulvodynia is a chronic vulvar pain condition affecting up to 8-16% of 18-60 year-old women. Epidemiological studies have associated an increased risk of developing vulvodynia with a history of seasonal and insect allergies. We have previously demonstrated that acute labiar exposure to the hapten allergen oxazolone provokes increased vulvar mechanical sensitivity in ND4 Swiss mice. Here, we show that repeated oxazolone challenge produces persistent vulvar mechanical sensitivity in sensitized mice for at least12 days after 10 allergen exposures. This persistent sensitivity is accompanied by mast cell accumulation and overgrowth of cutaneous neurites both of which persist for at least 14 days after the final allergen exposure. These changes are accompanied by an early and transient increase in mRNAs encoding CADM1 - an adhesion molecule that facilitates nerve-mast cell synapses - in the skin and mRNAs encoding the inflammatory cytokine IL-6 in the spinal cord. Taken together, these neuroimmune biomarkers may serve as potential diagnostic/therapeutic targets for specific allergy-driven subsets of chronic vulvar pain.