DESCRIPTION: Interstitial cystitis (IC) and vulvovestibulitis (VV) are idiopathic, painful, inflammatory disorders of endodermal sinus-derived structures. Clinically, they are characterized by an abnormal painful response to stretch of the bladder or vestibule, respectively, and many patients manifest both disorders.There is data to suggest that this pain and inflammation may be the result of abnormal activation of normally "silent" C-fibers. Substance P released locally from nerve terminals at the time of afferent firing can activate mast cells and endothelial cells to release mediators and cause inflammation. The neurotoxin, capsaicin, found in hot peppers, can selectively block or destroy C-fiber terminals, thereby eliminating pain and inflammation whilst preserving other sensory functions. We hypothesize that topical capsaicin can produce durable relief of pain and inflammation in both conditions through depletion of substance P in C-fibers and prevention of secondary release of inflammatory mediators. Our long-term objectives are i) to show that topical capsaicin is a safe and effective therapy for both IC and W and ii) to show that C-fiber function is an essential part of the pathogenesis of pain and inflammation in these disorders. Our aims are a) to determine the optimal concentration of capsaicin which can be safely instilled into the bladder, b) to determine the efficacy of topical capsaicin for vulvovestibulitis, c) to compare C-fiber density and substance P levels in bladder mucosa and vulvar skin before and after capsaicin treatment, and d) to determine if capsaicin-evoked depletion of C-fibers leads to a secondary reduction in the release of prostaglandin E2 and histamine into the skin in vulvovestibulitis and into bladder mucosa and urine in interstitial cystitis. In IC patients, a randomized, controlled, dose- titration study of intravesical capsaicin will be carried out with pre- and post treatment comparisons of bladder capacity, pain, and other symptoms. In addition, mucosal substance P content measured by radioimmunoassay, neuronal substance P labelling by immunocytochemistry and urinary concentration of prostaglandin E2 and histamine will be measured in bladder biopsies and urine following bladder distension before and after capsaicin treatment. We expect that capsaicin will eliminate the painful response to bladder distension and will preserve normal voiding and that this effect will be associated with a depletion of mucosal substance P, a reduction in the number of mucosal C-fibers, and elimination of the secondary release of prostaglandin E2 and histamine into the urine after bladder distension.