Overactive bladder (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) are diseases with unknown pathology and etiology. OAB and IC/BPS have devastating psychological and social impacts on quality of life, but treatments for these diseases are clinically challenging. Sacral neuromodulation is a FDA approved treatment for OAB. Currently it is only offered to OAB patients after pharmacotherapy has failed. Since its FDA approval for OAB, sacral neuromodulation has been shown to be effective in treating IC/BPS in many clinical trials and is currently listed in the AUA guideline o IC/BPS as one of the suggested treatment options. In addition clinical studies have showed that pudendal neuromodulation is superior to sacral neuromodulation. It successfully treated OAB or IC/BPS patients who have failed sacral neuromodulation. Furthermore, recent multicenter clinical trials have indicated that tibial neuromodulation is effective for treatment of OAB. Although neuromodulation is an effective treatment for OAB or IC/BPS, the mechanism underlying neuromodulation (sacral, pudendal, or tibial) is still unknown. More surprisingly there is very limited effort in basic science research aimed at revealing the mechanism of action underlying neuromdulation. In this project we propose to determine the central sites of action for neuromodulation by answering the following questions: 1. whether neuromodulation acts in the spinal cord or in the brain? 2. Whether it acts on the ascending or descending limbs of the spinobulbospinal micturition reflex pathway activated by bladder A?-fiber afferents or on the spinal micturition reflex pathway activated by noxious C-fiber bladder afferents? 3. What neurotransmitters are involved in neuromodulation? 4. How brain sensory and motor activity associated with bladder nociception/overactivity is altered by neuromodulation? Different neuromodulation methods (sacral, pudendal, or tibial) will be investigated and compared to answer these questions. Identifying the sites of action for different neuromodulation therapies will surely guide clinicians and patients in selection of the optimal treatment strategies and thereby significantly improve the clinical outcomes in treating OAB or IC/BPS. Information about the sites of action and the neurotransmitter mechanisms underlying neuromodulation could also be useful in developing new drugs to treat OAB or IC/BPS. Our studies will significantly benefit millions of Americans suffering from OAB or IC/BPS.

Public Health Relevance

Overactive bladder (OAB) or interstitial cystitis/bladder pain syndrome (IC/BPS) has devastating psychological and social impacts on quality of life, but treatments for these diseases are clinically challenging. Neuromodulation is one of the treatment options currently available for OAB or IC/BPS. Our project will reveal the mechanisms underlying neuromodulation, improve the clinical outcomes of this therapy, provide new targets for drug development, and significantly benefit millions of Americans suffering from OAB or IC/BPS.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK094905-01A1
Application #
8433699
Study Section
Special Emphasis Panel (UGPP)
Program Officer
Mullins, Christopher V
Project Start
2013-06-01
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
1
Fiscal Year
2013
Total Cost
$228,750
Indirect Cost
$78,750
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Reese, Jeremy; Xiao, Zhiying; Schwen, Zeyad et al. (2014) Effects of duloxetine and WAY100635 on pudendal inhibition of bladder overactivity in cats. J Pharmacol Exp Ther 349:402-7
Xiao, Zhiying; Rogers, Marc J; Shen, Bing et al. (2014) Somatic modulation of spinal reflex bladder activity mediated by nociceptive bladder afferent nerve fibers in cats. Am J Physiol Renal Physiol 307:F673-9
Xiao, Zhiying; Reese, Jeremy; Schwen, Zeyad et al. (2014) Role of spinal GABAA receptors in pudendal inhibition of nociceptive and nonnociceptive bladder reflexes in cats. Am J Physiol Renal Physiol 306:F781-9