Vestibulodynia is the most prevalent form of vulvar pain in North American women, with approximately 10% of women suffering from this debilitating pain condition. The objective of the proposed research is to develop a mouse model of vestibulodynia in order to elucidate the physiological mechanisms underlying this pain condition. The research will empirically evaluate a leading hypothesis about the etiology of vestibulodynia, which posits that prolonged vulvovaginal inflammation initiates a chronic state of vulvar allodynia. The specific research aims are fourfold: (a) to conduct a longitudinal assessment of whether the frequency of vulvovaginal candidiasis is associated with changes in vulvar mechanical sensitivity testing;(b) to evaluate sensory fiber expression following chronic vulvovaginal inflammation, including nerve fiber density (via Pgp 9.5 immunohistochemistry) and markers of nociception (via calcitonin gene related peptide and the vanilloid receptor TRPV1);(c) to examine the immunological profile of vulvar tissue following chronic inflammation to reveal potential pain mechanisms, including an assessment of cytokine levels (IL-6 and IL- 8), and mast cell count in vulvovaginal tissue;and, (d) to evaluate the importance of the MC1R gene in the development of vulvar pain by applying the methodology to MC1R-deficient mutant mice.
These aims will be accomplished with a novel method of mechanical sensitivity testing whereby von Frey filaments are applied to the mouse vulva, located ventrally from the anogential ridge. This method has produced highly reliable findings in preliminary work. Mouse vulvar sensitivity will be assessed across four separate infections with C. albicans to mimic the human condition of recurrent vulvovaginal candidiasis (with treatment), with each post-infection vulvar sensitivity measurement taking place three weeks after negative cultures are obtained. Following the final behavioral testing session, mouse vulvar tissue will be assessed for nerve fiber density, and expression of pain fiber activation. This work aims to examine peripheral mechanisms of chronic vulvar pain and to evaluate a potential genetic risk factor for vulvar pain, thereby elucidating a way by which inflammation can initiate and sustain pathological pain. Importantly, the development of a successful model for provoked genital pain can enable a comprehensive investigation into the genetic and neurochemical mechanisms of vulvar pain to evaluate the efficacy of, and mechanisms underlying, current treatments for vulvar pain (e.g., topical capsaicin) and to stimulate the development of new pharmacological interventions.
| Farmer, Melissa A; Leja, Alison; Foxen-Craft, Emily et al. (2014) Pain reduces sexual motivation in female but not male mice. J Neurosci 34:5747-53 |
| Farmer, Melissa A; Taylor, Anna M; Bailey, Andrea L et al. (2011) Repeated vulvovaginal fungal infections cause persistent pain in a mouse model of vulvodynia. Sci Transl Med 3:101ra91 |
