An estimated 6 million women in the US suffer from vulvodynia. Provoked vestibulodynia, which typically is associated with vulvar vestibulitis, occurs most often in premenopausal women. This chronic pain syndrome is characterized by increased numbers of nociceptor axons usually localized to the posterior vestibule. Clinical evidence suggests that reproductive hormones influence the development and severity of vulvar vestibulitis syndrome (VVS). Aside from surgical excision of the hyperinnervated tissue, there are no effective therapies. This application proposes preclinical studies designed to characterize an animal model of VVS, and to use it to assess biological mechanisms that may be amenable to therapeutic targeting. We developed a rat model of VVS that replicates many clinical findings in humans. Small-volume injections of complete Freund's adjuvant into the rat posterior vestibule evoke persistent hypersensitivity and hyperinnervation.
In Aim1, we use this model to investigate neural consequences of vestibular inflammation, including sprouting and phenotype alterations. We will investigate the persistence of hyperinnervation and its correlation to mechanical vestibular sensitivity, and determine if our model shows behavior consistent with dyspareunia. We will assess whether estrogen, which alters normal patterns of nociceptor innervation, also affects development of hyperinnervation. We will build on preliminary findings that progesterone administered to juvenile rats causes persistent increases in sensory innervation density, and determine whether this augments development of vestibular hyperinnervation. We will assess the extent to which our model simulates human cytological changes by comparing findings in rats with tissue excised from patients with VVS.
In Aim 2, we test the hypothesis that activation of the angiotensin II receptor type 2 (AT2) mediates hyperinnervation and hypersensitivity in VVS. In preliminary studies, we show that AT2 blockade abrogates hyperinnervation and hypersensitivity in our model. We hypothesize that inflammatory cells create a local renin-angiotensin system that synthesizes angiotensin II, which initiates sensory axon sprouting. We will determine if angiotensin II is synthesized by rat and human vestibular tissue, and using explant cultures, that it elicits sprouting. We will determine i AT2 activation in the absence of inflammation elicits sprouting and hypersensitivity in our rat model. We will determine if AT2 antagonism not only prevents, but also reverses hyperinnervation and hypersensitivity. We will determine if AT2 blockade is overcomes hyperinnervation and mechanical sensitivity augmented by the actions of reproductive hormones. This application will provide fundamental information on mechanisms that regulate innervation in normal and inflamed vestibular tissue. It employs a novel rat model to identify the biological underpinnings of vestibular inflammatory hypersensitivity with the intention of manipulating a key signaling pathway in order to identify new therapeutic targets in VVS. Information obtained in these studies has strong potential to substantively change our thinking and clinical approach to the management of some forms of vulvodynia.

Public Health Relevance

Vulvodynia affects approximately 16% of the adult US female population, but is poorly understood and there are limited treatments. This project uses both a rat model and tissues from affected patients to investigate a novel mechanism that may explain one of the key features of this disorder: an abnormally high number of pain-sensing nerves. We also investigate a potential therapeutic target which we have found to reduce nerve numbers and hypersensitivity.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
4R01HD049615-10
Application #
9104180
Study Section
Urologic and Genitourinary Physiology and Pathology (UGPP)
Program Officer
Tingen, Candace M
Project Start
2006-04-16
Project End
2017-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
10
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Kansas
Department
Physiology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Chakrabarty, Anuradha; Liao, Zhaohui; Mu, Ying et al. (2018) Inflammatory Renin-Angiotensin System Disruption Attenuates Sensory Hyperinnervation and Mechanical Hypersensitivity in a Rat Model of Provoked Vestibulodynia. J Pain 19:264-277
Liao, Zhaohui; Chakrabarty, Anuradha; Mu, Ying et al. (2017) A Local Inflammatory Renin-Angiotensin System Drives Sensory Axon Sprouting in Provoked Vestibulodynia. J Pain 18:511-525
Bhattacherjee, Aritra; Mu, Ying; Winter, Michelle K et al. (2017) Neuronal cytoskeletal gene dysregulation and mechanical hypersensitivity in a rat model of Rett syndrome. Proc Natl Acad Sci U S A 114:E6952-E6961
Bhattacherjee, Aritra; Winter, Michelle K; Eggimann, Linda S et al. (2017) Motor, Somatosensory, Viscerosensory and Metabolic Impairments in a Heterozygous Female Rat Model of Rett Syndrome. Int J Mol Sci 19:
Mónica Brauer, M; Smith, Peter G (2015) Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity. Auton Neurosci 187:1-17
Doss, Argenia L N; Smith, Peter G (2014) Langerhans cells regulate cutaneous innervation density and mechanical sensitivity in mouse footpad. Neurosci Lett 578:55-60
Bhattacherjee, Aritra; Liao, Zhaohui; Smith, Peter G (2014) Trophic factor and hormonal regulation of neurite outgrowth in sensory neuron-like 50B11 cells. Neurosci Lett 558:120-5
Tague, S E; Smith, P G (2014) Vitamin D deficiency leads to sensory and sympathetic denervation of the rat synovium. Neuroscience 279:77-93
Liao, Zhaohui; Smith, Peter G (2014) Persistent genital hyperinnervation following progesterone administration to adolescent female rats. Biol Reprod 91:144
Chakrabarty, Anuradha; Liao, Zhaohui; Smith, Peter G (2013) Angiotensin II receptor type 2 activation is required for cutaneous sensory hyperinnervation and hypersensitivity in a rat hind paw model of inflammatory pain. J Pain 14:1053-65

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