Repeated Vulvovaginal Fungal Infections Cause Persistent Pain in a Mouse Model of Vulvodynia

Abstract

Provoked vestibulodynia, the most common form of vulvodynia (unexplained pain of the vulva), is a prevalent, idiopathic pain disorder associated with a history of recurrent candidiasis (yeast infections). It is characterized by vulvar allodynia (painful hypersensitivity to touch) and hyperinnervation. We tested whether repeated, localized exposure of the vulva to a common fungal pathogen can lead to the development of chronic pain. A subset of female mice subjected to recurrent Candida albicans infection developed mechanical allodynia localized to the vulva. The mice with allodynia also exhibited hyperinnervation with peptidergic nociceptor and sympathetic fibers (as indicated by increased protein gene product 9.5, calcitonin gene–related peptide, and vesicular monoamine transporter 2 immunoreactivity in the vaginal epithelium). Long-lasting behavioral allodynia in a subset of mice was also observed after a single, extended Candida infection, as well as after repeated vulvar (but not hind paw) inflammation induced with zymosan, a mixture of fungal antigens. The hypersensitivity and hyperinnervation were both present at least 3 weeks after the resolution of infection and inflammation. Our data show that infection can cause persistent pain long after its resolution and that recurrent yeast infection replicates important features of human provoked vulvodynia in the mouse.

Measuring Changes in Tactile Sensitivity in the Hind Paw of Mice Using an Electronic von Frey Apparatus

“…The EvF protocol can easily be modified for use on tissues other than the hind paw e.g. abdomen 7 and ano-genital ridge 8 where CvF is currently used. Rodent models of allergies, wound healing, neuropathies and other pathologies can be easily adapted to include measures of mechanical sensitivity in tissues including and beyond the hind paw.…”

“…Reduction in time and intensity of previously specified responses to noxious stimuli are used to measure pain states in these animals as rodent subjects are not otherwise able to report a sensation of pain 6 . Altered responses to temperature and pressure are commonly used as metrics of tissue sensitivity in rodent models of inflammatory nociception that can be caused by infection 7,8 , chemical exposure 6,9,10 , surgical incision 11 , as well as neuropathic pain caused by nerve ligation 12 …”

Sympathetic Fiber Sprouting in Inflamed Joints and Adjacent Skin Contributes to Pain-Related Behavior in Arthritis

“…Error bars represent the SEM. Farmer et al, 2011) and involves different inflammatory components such as infiltration and degranulation of mast cells (Toyoda et al, 1994), neurogenic inflammation (Nakamura et al, 2003), plasma extravasation (Otten et al, 1984), and increased levels of proinflammatory cytokines (Darsow et al, 1997;Nakamura et al, 2003). The above changes are known to induce a substantial increase in NGF expression.…”

Female Sexual Pain Disorders: a Review of the Literature on Etiology and Treatment

“…Third, it has also been postulated that an inability to clear vulvovaginal infections and the resulting inflammation may lead to the development of vulvodynia. Although the literature contains inconsistent histopathological findings [43,46,44,47], the former point is supported by an experimental mouse model of vulvodynia that confirmed that repeated vulvovaginal infections with Candida albicans led to chronic vulvar pain behavior and increased vulvar innervation [48]. Finally, vulvodynia may be associated with some degree of pelvic floor muscle dysfunction.…”