Early experience has been shown to have a profound impact on the prevalence of chronic pain, particularly within the viscerosensory system. Preterm neonates are exposed to numerous stressors, including repeated invasive procedures (often without adequate anesthesia) and prolonged periods of maternal separation. Models of neonatal stress in rats, generated by either maternal separation or unpredictable shock, produce visceral hyperalgesia, as do neonatal rats that receive noxious mechanical or chemical irritation of the colon or bladder during the second week of life. The focus of this proposal is to determine how neonatal stress or irritation affects nociceptive processing from the vulva and vagina of adult mice and whether ablation of a select population of sensory neurons can normalize vulvovaginal sensation. Vulvodynia is clinically defined as chronic discomfort or pain of the vulva, often occurring as burning, stinging or soreness, in the absence of specific pathology or neurological disorder. Despite an estimated 15% of women experiencing chronic or evoked vulvovaginal pain lasting at least 3 months, relatively few published studies have investigated changes in vulvovaginal innervation and no animal models exist in the current literature. The experiments in this application are outlined in two specific aims designed to 1) determine how neonatal stress or irritation impacts vulvovaginal sensitivity and the nociceptive phenotype of sensory neurons innervating the affected tissue and 2) employ growth factor-conjugated saporin to selectively silence those fibers responsible for pain sensations as a preclinical test for treating vulvodynia in humans. Successful completion of these studies will not only provide the first published model of vulvodynia, but is also the first step in developing a new class of compounds that alleviates chronic pelvic pain without affecting normal sensations. Considering the high degree of comorbidity between vulvodynia and other chronic pelvic pain syndromes, e.g. endometriosis, irritable bowel syndrome and interstitial cystitis, chemical ablation of this population of nociceptors could also alleviate symptoms of these syndromes, as well.

Public Health Relevance

The focus of this proposal is how neonatal stress or irritation can permanently enhance pain signaling from the vulva and vagina. Current therapies for treating vulvodynia are either slow to show symptomatic improvement or require resection of affected tissue. We have proposed a novel therapy for silencing those nerves mediating painful sensations as a means of treating persistent pelvic pain.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
Project #
Application #
Study Section
Special Emphasis Panel (ZRR1-RI-B)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kansas
Kansas City
United States
Zip Code
Tran, Pamela V; Sharma, Madhulika; Li, Xiaogang et al. (2014) Developmental signaling: does it bridge the gap between cilia dysfunction and renal cystogenesis? Birth Defects Res C Embryo Today 102:159-73
Cha, Jeeyeon; Bartos, Amanda; Park, Craig et al. (2014) Appropriate crypt formation in the uterus for embryo homing and implantation requires Wnt5a-ROR signaling. Cell Rep 8:382-92
Pierce, A N; Ryals, J M; Wang, R et al. (2014) Vaginal hypersensitivity and hypothalamic-pituitary-adrenal axis dysfunction as a result of neonatal maternal separation in female mice. Neuroscience 263:216-30
Kumar, T Rajendra (2014) The quest for male germline stem cell markers: PAX7 gets ID'd. J Clin Invest 124:4219-22
Rumi, M A Karim; Dhakal, Pramod; Kubota, Kaiyu et al. (2014) Generation of Esr1-knockout rats using zinc finger nuclease-mediated genome editing. Endocrinology 155:1991-9
Tan, Ee Phie; Villar, Maria T; E, Lezi et al. (2014) Altering O-linked ?-N-acetylglucosamine cycling disrupts mitochondrial function. J Biol Chem 289:14719-30
Saadi, Irfan; Das, Pragnya; Zhao, Minglian et al. (2013) Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development. Development 140:2697-702
Dasouki, Majed J; Rafi, Syed K; Olm-Shipman, Adam J et al. (2013) Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia. Blood 122:3440-9
Taniguchi, Cullen M; Finger, Elizabeth C; Krieg, Adam J et al. (2013) Cross-talk between hypoxia and insulin signaling through Phd3 regulates hepatic glucose and lipid metabolism and ameliorates diabetes. Nat Med 19:1325-30
Abrahamson, Dale R; St John, Patricia L; Stroganova, Larysa et al. (2013) Laminin and type IV collagen isoform substitutions occur in temporally and spatially distinct patterns in developing kidney glomerular basement membranes. J Histochem Cytochem 61:706-18

Showing the most recent 10 out of 11 publications