Electrophysiologic, pharmacologic and neurochemical techniques will be used to examine the mechanisms underlying the neural detection of noxious stimuli in the lower urinary tract. We areparticularly interested in identifying the chemical mediators which sensitize bladder, nociceptors and how these chemical mediators alter ion channels in afferent neurons and thereby change afferent receptor excitability. We will also examine changes in afferent neurons induced by chronic pathological conditions that result in bladder irritation and hyperactivity. Several hypotheses will be tested: (1) Several subtypes of nociceptors are present in the bladder wall and these subtypes exhibit distinct electrophysiologic properties arid-distinct receptive/signaling mechanisms, (2) Acute sensitization of bladder nociceptors involves a change in several membrane ion channels including: tetrodotoxin-resistant Na+ channels, yanilloid receptors (VRl) which are sensitive to capsaicin, ATP-sensitive purinergic receptors, fast activation R+ channels and acid sensitive cation channels (ASIC), (3) Chronic pathological conditions of the lower urinary tract alter the expression of ion channels or neurotransmitter mechanisms in afferent neurons. This effect may be mediated by neurotrophic factors released within the bladder, (4) Bidirectional chemical communication between the urothelium and adjacent nerves plays a role in sensory mechanisms as well as in epithelial cell function in the urinary tract. The long-term objectives of the research program are to understand the mechanisms by which irritating or tissue-injuring stimuli are detected and processed by the nervous system and in turn modulate urinary tract function. The contribution of the urothelium to sensory processing will receive particular attention. The ultimate goal is to identify new molecular targets for drug therapy of bladder pain. PERFORMANCE SfTE(S) (organization, dry, state) Department of Pharmacology, Medical School, University of Pittsburgh Pittsburgh, PA, 15261 KEY PERSONNEL See instructions on Page 11. Use continuation pages as neededto provide the required information in the format shown below. Name Organization Role on Project William C. de Groat University of Pittsburgh PI Adrian Sculptoreanu " " Res. Associate Alyssa Hawranko Naoki Yoshimura " " Res. Ass. Prof. Kyu-Sung Lee " " Res. Associate Yao-Chi Chuang " " Visiting Ass. Prof. Jon Beckel " " Res. Assistant PHS 398 (Rev. 4/98) Page 2 BB Number pages consecutivelyat the bottomthroughout the application. Dorjoj use suffixes suchas 3a, 3b. cc Principal Investigator/Program Director (Last, first, middle): de Groat, William C. Type the name of the principal investigator/proj^^ director at the top of each printed page and eachJ^tinuation page. (Fortype specifications, see instructions on page 6.) ^Ir ^P \ [unreadable] u- RESEARCH GRANT TABLE OF CONTENTS Page Numbers Face Page..: :.. ; 1 Description,