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

Department of Psychology, McGill University, 1205 Doctor Penfield Avenue, Montreal, Quebec H3A 1B1, Canada.
Science translational medicine (Impact Factor: 15.84). 09/2011; 3(101):101ra91. DOI: 10.1126/scitranslmed.3002613
Source: PubMed


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.

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Available from: Halley Crissman, Jul 10, 2014
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    • "To measure vulvar sensitivity, mice were stimulated along the ano-genital ridge with a semi-flexible polypropylene tip fitted to an electronic von Frey pressure meter (IITC Life Science, Woodland Hills, CA) until they demonstrated one or more nociceptive behaviors: genital licking, lower abdomen retraction, a back paw jump, or a four paw jump [15]. Baseline measurements were taken 24 and 48 hours before sensitization; of 5 baseline measurements per mouse, three closest to the median were averaged to obtain the baseline withdrawal threshold as previously described [16]. "
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    ABSTRACT: 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.
    PLoS ONE 10/2013; 8(10):e78673. DOI:10.1371/journal.pone.0078673 · 3.23 Impact Factor
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    • "The causal relationship between RVVC and vestibular vulvodynia is not clear. Vestibular vulvodynia could be a symptom of RVVC or a comorbidity triggered by RVVC as suggested by a recent report [41], although this pain syndrome may also have other origins. "
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    ABSTRACT: Recurrent vulvovaginal candidosis (RVVC) is a chronic condition causing discomfort and pain. Health status and health-related quality of life (HRQoL) in RVVC were never previously described using validated questionnaires. The objective of this study is to describe subjective health status and HRQoL and estimate health state utilities among women with RVVC. A cross-sectional online survey was conducted among women who reported having suffered four or more yeast infections over the past 12 months, in five European countries (France, Germany, Italy, Spain and the UK) and the USA. Index scores were derived from the EQ-5D, a questionnaire providing a single index value for health status. The SF-36 questionnaire was used for HRQoL assessment. Information on disease severity, treatment patterns and productivity was also collected. 12,834 members of online research panels were contacted. Among them, 620 women with RVVC (5%) were selected to complete the full questionnaire. The mean EQ-5D index score was 0.70 (95% confidence interval: [0.67, 0.72]) and the difference between women with a yeast infection at the time of questionnaire completion and other respondents was 0.05 (p = 0.47). The EQ-5D index score increased significantly with the time since last infection (p < 0.001). 68% of women reported depression/anxiety problems during acute episode, and 54% outside episodes, compared to less than 20% in general population (p < 0.001). All SF-36 domain scores were significantly below general population norms. Mental health domains were the most affected. The impact on productivity was estimated at 33 lost work hours per year on average, corresponding to estimated costs between [euro sign]266/year and [euro sign]1,130/year depending on the country. Subjective health status and HRQoL during and in between acute inflammatory episodes in women with RVVC are significantly worse than in the general population, despite the use of antifungal therapy. The average index score in women with RVVC is comparable to other diseases such as asthma or COPD and worse than diseases such as headache/migraine according to US and UK catalogs of index scores. The survey also revealed a significant loss of productivity associated with RVVC.
    Health and Quality of Life Outcomes 10/2013; 11(1):169. DOI:10.1186/1477-7525-11-169 · 2.12 Impact Factor
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    • "The populations of nerve fibers that are undergoing sprouting include CGRP+ and NF200+ sensory nerve fibers that correspond to unmyelinated/thinly myelinated and thinly myelinated sensory nerve fibers, respectively, as well as TH+ postganglionic sympathetic nerve fibers. Previous human [57-69] and rodent [23,35,46,70-74] studies have shown that inappropriate remodeling of sensory and sympathetic nerve fibers can be associated with skeletal [23,35,46,62,63,68,69,71] and nonskeletal pain [57,60,64-67,72-74]. As we observed a similar remodeling of sensory and sympathetic nerve fibers in geriatric arthritic knee joints, this pathologic reorganization of nerve fibers would then set in place a neuroanatomic substrate that could drive movement and resting arthritic joint pain. "
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    ABSTRACT: Although the prevalence of arthritis dramatically increases with age, the great majority of preclinical studies concerning the mechanisms that drive arthritic joint pain have been performed in young animals. One mechanism hypothesized to contribute to arthritic pain is ectopic nerve sprouting; however, neuroplasticity is generally thought to be greater in young versus old nerves. Here we explore whether sensory and sympathetic nerve fibers can undergo a significant ectopic nerve remodeling in the painful arthritic knee joint of geriatric mice. Vehicle (saline) or complete Freund's adjuvant (CFA) was injected into the knee joint of 27- to 29-month-old female mice. Pain behaviors, macrophage infiltration, neovascularization, and the sprouting of sensory and sympathetic nerve fibers were then assessed 28 days later, when significant knee-joint pain was present. Knee joints were processed for immunohistochemistry by using antibodies raised against CD68 (monocytes/macrophages), PECAM (endothelial cells), calcitonin gene-related peptide (CGRP; sensory nerve fibers), neurofilament 200 kDa (NF200; sensory nerve fibers), tyrosine hydroxylase (TH; sympathetic nerve fibers), and growth-associated protein 43 (GAP43; nerve fibers undergoing sprouting). At 4 weeks after initial injection, CFA-injected mice displayed robust pain-related behaviors (which included flinching, guarding, impaired limb use, and reduced weight bearing), whereas animals injected with vehicle alone displayed no significant pain-related behaviors. Similarly, in the CFA-injected knee joint, but not in the vehicle-injected knee joint, a remarkable increase was noted in the number of CD68+ macrophages, density of PECAM+ blood vessels, and density and formation of neuroma-like structures by CGRP+, NF200+, and TH+ nerve fibers in the synovium and periosteum. Sensory and sympathetic nerve fibers that innervate the aged knee joint clearly maintain the capacity for robust nerve sprouting and formation of neuroma-like structures after inflammation/injury. Understanding the factors that drive this neuroplasticity, whether this pathologic reorganization of nerve fibers contributes to chronic joint pain, and how the phenotype of sensory and sympathetic nerves changes with age may provide pharmacologic insight and targets for better controlling aging-related joint pain.
    Arthritis research & therapy 05/2012; 14(3):R101. DOI:10.1186/ar3826 · 3.75 Impact Factor
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