The functions of the lower urinary tract to store and periodically release urine depend on neural circuits located in the brain and lumbosacral spinal cord. Severe injury to the spinal cord rostral to the lumbosacral level eliminates voluntary and supraspinal control of voiding, leading initially to an areflexic bladder and complete urinary retention. This period of reflex suppression is followed by the emergence of automatic (reflex) micturition and bladder hyperactivity mediated by spinal pathways. However, voiding in spinal cord injured patients is usually inefficient due to uncoordinated activity of the bladder and urethral sphincter (bladder-sphincter dyssynergia). The long-term objective of the studies is to identify the neural circuitry that mediates lower urinary tract dysfunction after spinal injury. It is expected that a detailed understanding of the chemical properties of this circuitry, including neurotransmitter mechanisms, will facilitate the development of new therapies for the treatment of neurogenic bladder disorders. Neuroanatomical, electrophysiological and pharmacological experiments will be conducted in chronic spinal cord transected cats because this model has provided important insights into the mechanisms that underlie the recovery of bladder activity after spinal injury. Previous studies in chronic paraplegic animals revealed a marked reorganization of bladder reflex pathways and focused attention on the role of unmyelinated (C-fiber) bladder afferents in triggering spinal voiding reflexes. This has led to the testing of new treatments, such as intravesical administration of C-fiber afferent neurotoxins (capsaicin and RTX), for the management of bladder hyperreflexia and incontinence in patients with neurogenic bladder disorders. Based on animal and human data, it is hypothesized that detrusor hyperreflexia after cord injury occurs as a result of plasticity in spinal interneuronal circuitry as well as in primary afferent neurons. The project will examine the mechanisms underlying this plasticity with the goal of identifying new molecular targets for the pharmacotherapy of neurogenic voiding dysfunction.
Specific aims i nclude: (1) characterization of the synaptic reorganization in spinal interneuronal pathways that mediates the recovery of voiding function in chronic paraplegic cats; (2) evaluation, with electrophysiological techniques, of the properties of A-delta and C-fiber bladder afferent neurons and the changes which underlie the emergence of mechanosensitivity in C-fiber afferent receptors after spinal injury; and (3) examination of the putative role of the urothelium in sensory transduction mechanisms and how changes in the urothelium might contribute to altered afferent sensitivity in paraplegic cats.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Program Projects (P01)
Project #
Application #
Study Section
National Institute of Child Health and Human Development Initial Review Group (CHHD)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
United States
Zip Code
Visus, Carmen; Ito, Diasuke; Dhir, Rajiv et al. (2011) Identification of Hydroxysteroid (17?) dehydrogenase type 12 (HSD17B12) as a CD8+ T-cell-defined human tumor antigen of human carcinomas. Cancer Immunol Immunother 60:919-29
Yin, Bo; Yang, Yang; Zhao, Zhiqiang et al. (2011) Arachidonate 12-lipoxygenase may serve as a potential marker and therapeutic target for prostate cancer stem cells. Int J Oncol 38:1041-6
de Groat, William C; Yoshimura, Naoki (2010) Changes in afferent activity after spinal cord injury. Neurourol Urodyn 29:63-76
Miyazato, M; Sugaya, K; Goins, W F et al. (2009) Herpes simplex virus vector-mediated gene delivery of glutamic acid decarboxylase reduces detrusor overactivity in spinal cord-injured rats. Gene Ther 16:660-8
Wognum, Silvia; Lagoa, Claudio E; Nagatomi, Jiro et al. (2009) An exploratory pathways analysis of temporal changes induced by spinal cord injury in the rat bladder wall: insights on remodeling and inflammation. PLoS One 4:e5852
Hayashi, Yukio; Takimoto, Koichi; Chancellor, Michael B et al. (2009) Bladder hyperactivity and increased excitability of bladder afferent neurons associated with reduced expression of Kv1.4 alpha-subunit in rats with cystitis. Am J Physiol Regul Integr Comp Physiol 296:R1661-70
Wognum, Silvia; Schmidt, David E; Sacks, Michael S (2009) On the mechanical role of de novo synthesized elastin in the urinary bladder wall. J Biomech Eng 131:101018
Wang, Chung Cheng; Nagatomi, Jiro; Toosi, K Khashayar et al. (2009) Diabetes-induced alternations in biomechanical properties of urinary bladder wall in rats. Urology 73:911-5
Miyazato, Minoru; Sasatomi, Kurumi; Hiragata, Shiro et al. (2008) GABA receptor activation in the lumbosacral spinal cord decreases detrusor overactivity in spinal cord injured rats. J Urol 179:1178-83
Yoshimura, Naoki; Kaiho, Yasuhiro; Miyazato, Minoru et al. (2008) Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol 377:437-48

Showing the most recent 10 out of 72 publications