The interplay among pain, allergy and dysregulated inflammation promises to yield significant conceptual advances in immunology and chronic pain. Hapten-mediated contact hypersensitivity reactions are used to model skin allergies in rodents but have not been utilized to study associated changes in pain perception in the affected skin. Here we characterized changes in mechanical hyperalgesia in oxazolone-sensitized female mice challenged with single and repeated labiar skin exposure to oxazolone. Female mice were sensitized with topical oxazolone on their flanks and challenged 1-3 times on the labia. We then measured mechanical sensitivity of the vulvar region with an electronic pressure meter and evaluated expression of inflammatory genes, leukocyte influx and levels of innervation in the labiar tissue. Oxazolone-sensitized mice developed vulvar mechanical hyperalgesia after a single labiar oxazolone challenge. Hyperalgesia lasted up to 24 hours along with local influx of neutrophils, upregulation of inflammatory cytokine gene expression, and increased density of cutaneous labiar nerve fibers. Three daily oxazolone challenges produced vulvar mechanical hyperalgesic responses and increases in nerve density that were detectable up to 5 days post-challenge even after overt inflammation resolved. This persistent vulvar hyperalgesia is resonant with vulvodynia, an understudied chronic pain condition that is remarkably prevalent in 18-60 year-old women. An elevated risk for vulvodynia has been associated with a history of environmental allergies. Our pre-clinical model can be readily adapted to regimens of chronic exposures and long-term assessment of vulvar pain with and without concurrent inflammation to improve our understanding of mechanisms underlying subsets of vulvodynia and to develop new therapeutics for this condition.

Vulvodynia can affect ~20% of women of child-bearing age. Activities such as contact with tight clothing or sexual intercourse provoke burning pain sensations whose etiology and underlying mechanisms are poorly understood. Epidemiological evidence suggests a link between a history of environmental allergies and the risk of developing vulvodynia. Clinicians find increased mast cell numbers, hyperinnervation and up-regulation of inflammatory cytokines in biopsies from vulvodynia patients vs. controls. An allergy-based mast cell focused mouse model of vulvodynia is needed to elucidate the mechanisms underlying this pathology. We show that challenge with contact hypersensitivity allergen oxazolone produces acute mechanical hyperalgesia in the vulvar region of previously sensitized female mice. Acute pain is localized to the challenge site, lasts up to 24 hours post-challenge and is accompanied by influx of neutrophils into the labiar tissue and up-regulation of several inflammatory cytokine genes including IL-6, Cxcl-1 and Cxcl-2. Pre-challenge administration of H1R-antagonist pyrilamine, tricyclic antidepressant amitryptiline, and sodium cromoglycate all abrogate the hyperalgesic response. Our findings provide the first evidence of the induction of measurable pain following an allergic response in the labiar/vulvar tissue in mice thus establishing a model that can be adapted to chronic challenges and long-term assessment of pain with and without ongoing inflammation.