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.

Public Health Relevance

Localized provoked vulvodynia is the most common cause of painful intercourse in premenopausal women. This research project is focused on discovering the root cause of the pain. Excitingly, we have found that certain natural compounds have the ability to diminish the pain by dampening the ability of cells, called fibroblasts, to produce substances that cause pain. Our goal is to test whether or not these naturally occurring compounds will quench the fires of vulvodynia.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD092334-02
Application #
9784899
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Conroy, Jennie Lynn
Project Start
2018-09-13
Project End
2023-05-31
Budget Start
2019-06-01
Budget End
2020-05-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Rochester
Department
Obstetrics & Gynecology
Type
School of Medicine & Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627