Interstitial cystitis (IC) is a painful bladder disorder associated with irritative voiding systems and non-specific cystoscopic and pathologic findings. IC and other painful conditions affect over 300,000 Americans and account for substantial health care expense, yet are poorly understood and refractory to most therapies. The inability to detect a sole cause for IC may reflect multiple etiologies and/or a heterogeneous disorder. The sympathetic nervous system has been implicated in the pathogenesis and maintenance of several pain disorders including IC. Mechanisms for this involvement resemble those for reflex sympathetic dystrophy. We propose that IC is one of a number of pain disorders involving altered neural function and that different transient inflammatory stimuli can lead to short-term, and in some cases long-term, alterations in neural pathways to the bladder. The research proposed will demonstrate that inflammatory stimuli affect the morphology and function of sympathetic nerves in the bladder and pelvic ganglia and examine mechanisms initiating altered sympathetic innervation. Changes in the amount and distribution of peripheral sympathetic nerves in the rat bladder will be measured by norepinephrine content and catecholamine fluorescence after chemical, mechanical, bacterial and immunological irritation of the bladder. The function of sympathetic nerves to the bladder will be examined using in vitro muscle bath studies, and in vivo electrophysiologic and urodynamic preparations. Laser Doppler measurements of blood flow in the bladder wall will also be used to monitor the effect of hypogastric nerve and sympathetic chain stimulation on blood flow before and after inflammation. Immunohistochemical and morphological characterization of sympathetic neurons in the pelvic ganglia will also be undertaken. Synaptic transmission by sympathetic nerves in the pelvic ganglia will be investigated because alterations in sympathetic nerves may affect not only sensory nerves but also motor input to the bladder. These mechanisms may be accentuated following inflammation. The role of nerve growth factor (NGF) in inflammation-induced neural plasticity involving sympathetic pathways will be tested by blockade with receptor (trk A) antagonists and by induced immunity to endogenous NGF. Other experiments will determine the cellular sources of NGF in the bladder and whether urothelial cells interact with NGF-producing detrusor. By identifying the changes in sympathetic nerves and the mechanism for these alterations, this study will provide insight into how an inflammatory stimulus in the lower urinary tract alters neural function. Understanding the alterations in neural function may provide not only a mechanistic explanation for changes in bladder sensation, but may also lead to novel therapies for irritative disorders of the lower urinary tract.
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