Mechanisms of vulvodynia involving dysregulation of pro-resolving lipids

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The Focus: Localized provoked vulvodynia (LPV) is the most common cause of longstanding dyspareunia (painful sexual intercourse) in premenopausal women. Yet, LPV etiology is unclear, and no effective medical therapy exists; clinical trials report that treatments are no better in alleviating pain than placebo. LPV presents with pain to light touch limited to a defined region of the female lower genital tract termed the vulvar vestibule. The Premise: Our research team has discovered that fibroblast strains isolated from painful sites in the vulvar vestibule produce elevated levels of pro-pain and proinflammatory mediators (e.g. PGE2 and IL-6). When exposed to proinflammatory stimuli found in the vulvovaginal milieu, vestibular fibroblasts produce significantly higher levels of pro-pain signals than fibroblasts from pain-free sites a few millimeters away. This unique and intrinsic responsiveness connects innate vulvar responses to neuro-inflammation and culminates in localized, longstanding pain. Thus, LPV is likely an exacerbation of a normal anatomically-defined innate inflammatory response. Therapeutics that resolve inflammation and pain without impairing normal host defense (i.e. specialized pro-resolving mediators; SPMs) may be effective against LPV. SPMs are omega-3 and omega-6 fatty acid-derived lipids that consist of several types called, resolvins, maresins, protectins, and lipoxins. SPMs are naturally produced by the human body, have virtually no toxicity, and several are in clinical trial for inflammatory and other diseases, which could lead to faster clinical translation. Although SPMs have not been tested as an LPV therapy, we have strong supporting evidence that these lipids will be effective against LPV. Organizing Hypothesis: We hypothesize that SPMs will effectively modulate the LPV pathologic response and in turn, will successfully resolve LPV-associated neuro-inflammatory pain. Here, we will identify SPMs that are effective in reducing levels of proinflammatory mediators associated with LPV pain, define the mechanisms whereby SPMs act, their role(s) in LPV disease, and test therapeutic candidates in a preclinical LPV model. Specific Aim 1: Investigate the role of SPMs in blunting proinflammatory/pro-pain responses in vulvar fibroblasts, tissues, and fluids from controls and patients with LPV. Specific Aim 2: Determine the mechanism(s) that govern SPM production, responsiveness, and therapeutic potential in vulvar fibroblasts. Specific Aim 3: Evaluate the efficacy of SPMs in alleviating pain using a novel preclinical LPV mouse model. Impact on the field: We will make a significant step forward in identifying potential therapeutic agents that could not only reduce excessive proinflammatory signaling and pain in the context of LPV, but also in other chronic inflammatory conditions. Furthermore, we will strengthen the methodological basis for preclinical analgesia testing in LPV and identify SPM molecules that could be readily translated to clinical trials/use. No effective LPV therapies exist, making our work vital to improving treatment of this crippling condition.