Overactive bladder (OAB) is defined by the International Continence Society as a syndrome characterized by urgency with or without urge incontinence, usually with frequency and nocturia. The pathology and etiology of OAB currently remain unknown. OAB has devastating psychological and social impacts on quality of life, but treatments for OAB are clinically challenging. Sacral neuromodulation is a FDA approved treatment for OAB. Currently it is only offered to OAB patients after pharmacotherapy has failed. In addition, clinical studies have showed that pudendal neuromodulation is superior to sacral neuromodulation. It successfully treated OAB patients who have failed sacral neuromodulation. Furthermore, recent multicenter clinical trials have indicated that tibial neuromodulation is also effective for OAB treatment. Although neuromodulation is an effective treatment for OAB, the mechanisms underlying neuromodulation (sacral, pudendal, or tibial) are still unknown leaving neuromodulation as a mysterious therapy. More surprisingly there is very limited effort in basic science research aimed at revealing the possible mechanisms underlying neuromdulation. In this project we propose to elucidate the mechanisms underlying neuromodulation of bladder overactivity by answering the following question: what neurotransmitter receptors are involved in the different types of neuromodulation (sacral, pudendal, or tibial)? It would be na?ve to believe that the different neuromodulation therapies utilize the same neurotransmitter mechanisms to achieve the therapeutic effects on OAB conditions. Identifying the neurotransmitters/receptors involved in different neuromodulation therapies will remove the mysteries around bladder neuromodulation and provide basic science evidences. It will also provide new pharmacological interventions to further improve the efficacy of neuromodulation therapy. Information about the neurotransmitter mechanisms underlying neuromodulation could also be useful in developing new drugs to treat OAB. Our studies will significantly benefit millions of Americans suffering from OAB.

Public Health Relevance

Overactive bladder (OAB) has devastating psychological and social impacts on quality of life, but treatments for OAB are clinically challenging. Neuromodulation is an effective OAB treatment but its mechanism of action is currently unknown. Our project will identify neurotransmitter receptors involved in neuromodulation, which can be used to improve the clinical outcomes of this therapy, provide new targets for drug development, and significantly benefit millions of Americans suffering from OAB.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK102427-01
Application #
8739859
Study Section
Special Emphasis Panel (UGPP)
Program Officer
Bavendam, Tamara G
Project Start
2014-08-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
1
Fiscal Year
2014
Total Cost
$231,000
Indirect Cost
$81,000
Name
University of Pittsburgh
Department
Urology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Uy, Jamie; Yu, Michelle; Jiang, Xuewen et al. (2017) Glutamatergic Mechanisms Involved in Bladder Overactivity and Pudendal Neuromodulation in Cats. J Pharmacol Exp Ther 362:53-58
Jiang, Xuewen; Yu, Michelle; Uy, Jamie et al. (2017) Role of cannabinoid receptor type 1 in tibial and pudendal neuromodulation of bladder overactivity in cats. Am J Physiol Renal Physiol 312:F482-F488
Bandari, Jathin; Bansal, Utsav; Zhang, Zhaocun et al. (2017) Neurotransmitter Mechanisms Underlying Sacral Neuromodulation of Bladder Overactivity in Cats. Neuromodulation 20:81-87
Zhang, Zhaocun; Bandari, Jathin; Bansal, Utsav et al. (2017) Sacral neuromodulation of nociceptive bladder overactivity in cats. Neurourol Urodyn 36:1270-1277
Fuller, Thomas W; Jiang, Xuewen; Bansal, Utsav et al. (2017) Sex difference in the contribution of GABAB receptors to tibial neuromodulation of bladder overactivity in cats. Am J Physiol Regul Integr Comp Physiol 312:R292-R300
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Tennyson, Lauren E; Tai, Changfeng; Chermansky, Christopher J (2016) Using the Native Afferent Nervous System to Sense Bladder Fullness: State of the Art. Curr Bladder Dysfunct Rep 11:346-349
Kadow, Brian T; Lyon, Timothy D; Zhang, Zhaocun et al. (2016) Sympathetic ?-adrenergic mechanism in pudendal inhibition of nociceptive and non-nociceptive reflex bladder activity. Am J Physiol Renal Physiol 311:F78-84
Jiang, Xuewen; Fuller, Thomas W; Bandari, Jathin et al. (2016) Contribution of GABAA, Glycine, and Opioid Receptors to Sacral Neuromodulation of Bladder Overactivity in Cats. J Pharmacol Exp Ther 359:436-441
Fribance, Sarah; Wang, Jicheng; Roppolo, James R et al. (2016) Axonal model for temperature stimulation. J Comput Neurosci 41:185-92

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