Impact of Early Experience on Vulvovaginal Sensitivity in Adult Mouse

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PROJECT SUMMARY (See instructions): 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