Interstitial cystitis (IC) is a chronic lower urinary tract disorder characterized by urinary frequency, urgency, suprapubic pressure and pain. Although various pathological mechanisms have been proposed to account for IC, the etiology of the disorder is unknown. Nevertheless, it seems reasonable to speculate that IC is an abnormality of visceral sensation and that the IC patient is either more sensitive to relatively normal afferent activity generated in the bladder or that the bladder generates abnormal afferent signals in response to an unidentified peripheral pathology. The experiments in this proposal are designed to analyze the neural pathways transmitting nociceptive information from the bladder in rats and to evaluate the influence of noxious bladder stimuli on the properties of peripheral afferent neurons and spinal neurons that process sensory input from the lower urinary tract. Several hypotheses will be tested: (1) bladder pain is triggered by normally silent (sleeping) C-fiber afferents that are sensitized by chemical mediators released at sites of inflammation or tissue injury, (2) silent C-fibers are quiescent or insensitive to mechanical stimuli such as bladder distension due to a high threshold for activation of sodium currents as well as a low threshold for activation of a potassium current which tends to decrease cell excitability, (3) inflammatory and pain producing substances sensitize bladder afferents by blocking potassium channels, (4) chronic inflammation in the bladder can alter the properties of bladder afferents to increase their excitability and alter their chemistry, (5) interactions between sympathetic efferent pathways and afferent pathways can modulate sensory input from the bladder and may be a mechanism for sensitization of silent c-fibers, (6) allodynia, defined as a painful response to a normally nonpainful stimulus, can occur in the inflamed bladder as in other organs and may be mediated by both central and peripheral mechanisms. The long term objectives of this research program are to understand the mechanisms by which irritating or tissue injuring stimuli in the lower urinary tract are detected and processed by the nervous system and in turn modulate urinary tract function. The study will utilize a multidisciplinary approach encompassing neurochemistry, electrophysiology and pharmacology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK049430-05
Application #
2770508
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Project Start
1994-09-30
Project End
2000-02-29
Budget Start
1998-09-18
Budget End
2000-02-29
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
de Groat, William C; Yoshimura, Naoki (2012) Plasticity in reflex pathways to the lower urinary tract following spinal cord injury. Exp Neurol 235:123-32
Artim, Debra E; Kullmann, F Aura; Daugherty, Stephanie L et al. (2011) Developmental and spinal cord injury-induced changes in nitric oxide-mediated inhibition in rat urinary bladder. Neurourol Urodyn 30:1666-74
Kullmann, F Aura; Downs, Thomas R; Artim, Debra E et al. (2011) Urothelial beta-3 adrenergic receptors in the rat bladder. Neurourol Urodyn 30:144-50
Kanai, Anthony; Zabbarova, Irina; Ikeda, Youko et al. (2011) Sophisticated models and methods for studying neurogenic bladder dysfunction. Neurourol Urodyn 30:658-67
Buyuknacar, Hacer S G; Gocmen, Cemil; de Groat, William C et al. (2010) Differential effect of L-cysteine in isolated whole-bladder preparations from neonatal and adult rats. J Pharmacol Exp Ther 333:228-35
de Groat, William C; Yoshimura, Naoki (2010) Changes in afferent activity after spinal cord injury. Neurourol Urodyn 29:63-76
Yu, Yongbei; de Groat, William C (2010) Effects of stimulation of muscarinic receptors on bladder afferent nerves in the in vitro bladder-pelvic afferent nerve preparation of the rat. Brain Res 1361:43-53
Thor, Karl B; de Groat, William C (2010) Neural control of the female urethral and anal rhabdosphincters and pelvic floor muscles. Am J Physiol Regul Integr Comp Physiol 299:R416-38
Cheng, Chen-Li; de Groat, William C (2010) Role of 5-HT1A receptors in control of lower urinary tract function in anesthetized rats. Am J Physiol Renal Physiol 298:F771-8
Artim, Debra E; Kullmann, F Aura; Daugherty, Stephanie L et al. (2009) Activation of the nitric oxide-cGMP pathway reduces phasic contractions in neonatal rat bladder strips via protein kinase G. Am J Physiol Renal Physiol 297:F333-40

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