Bladder Regulation by Corticotropin-Releasing Factor

Childrens Hospital Of Philadelphia, Philadelphia PA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): This is an application for an Exploratory/Developmental Project in response to PA-03-136,"Basic Research in the Bladder and Lower Urinary Tract". Harrington's nucleus, a pentane nucleus with descending projections to lumbosacral preganglionic neurons, regulates parasympathetic outflow to the bladder. Bladder distention activates Barrington's nucleus, which then coordinates visceral (contraction) and central (arousal) responses to the stimulus. Corticotropin-releasing factor (CRF) is a prominent neurotransmitter in Barrington's nucleus neurons and is therefore poised to modulate urinary function. Moreover, pharmacological manipulation of CRF may provide a novel treatment of urinary dysfunctions. In spite of its prominence in the pontine micturition circuit, the role of CRF in micturition and the impact of manipulating CRF on urodynamic function remain unexplored. This proposal will determine the role of CRF in the pontine-spinal circuit (AIM 1) and whether manipulation of CRF in the spinal cord can improve urodynamic function that has been compromised by partial obstruction (AIM 2). Additionally, the impact of partial obstruction on components of the pontine micturition pathway will be identified (AIM 3). Cystometry will be used to quantify effects of selective activation or antagonism of CRF receptors in the spinal cord on urodynamics in unanesthetized rats with unobstructed or partially obstructed bladder. Conversely, the impact of bladder obstruction on single unit activity of Barrington's nucleus neurons, CRF mRNA expression in Barrington's nucleus neurons and CRF- receptor mRNA expression in the spinal cord will be quantified. These studies unite complementary expertise from laboratories in urology and basic neuroscience to increase our knowledge of the central regulation of urinary function in normal and pathological state. [unreadable] [unreadable]