Acute and chronic pains originating from the urinary bladder are common clinical entities affecting more than 50% of females at some time in their lives. Some conditions are easy to treat, but others, such as interstitial cystitis, are conditions of visceral hypersensitivity that have proven resistant to diagnosis and treatment. There are multiple proposed etiologies for visceral hypersensitivity conditions including mast cell functional abnormalities, immunologic abnormalities, urothelial abnormalities and primary neuropathic mechanisms but the common theme among them is an eventual sensitization/activation of sensory elements. Abnormalities in the periphery leads to central neurophysiological changes that become expressed as enhanced sensory (pain-urgency) and reflex responses (i.e. reduced bladder capacity) which may outlast """"""""triggering"""""""" events within the bladder. This proposal defines the consequences of altered primary afferent function by examining the spinal sites of sensory processing which magnify and prolong the effects of peripheral processes. The hypothesis central to these studies is the following: ? ? Pathological urinary bladder pain occurs secondary to a spinal sensitization process produced by repeated or continuous primary afferent activation which leads to a hypersensitivity state in which previously innocuous stimuli produce pain. ? ? To delineate mechanisms of this sensitization process, testable hypotheses are proposed: first, that sensitization occurs secondary to the selective activation of one of two spinal dorsal horn neuronal populations; second, that a driving force of this sensitization process is the activation of peripheral K-opioid receptor expressing primary afferents; and finally, it is proposed that spinal neurons which are selectively activated by visceral pain-producing manipulations have axonal projections located in the mid-dorsal spinal cord. To test the critical aspects of these hypotheses, neuronal and physiological responses to urinary bladder distension will be studied. Information gathered as part of these studies will allow for an improved definition of urinary bladder-related spinal nociceptive processing mechanisms and will suggest novel therapeutic interventions for urinary bladder pain which include the use of peripherally acting analgesics and modulation/interruption of selective pain pathways. To allow for methodological expansion, characterization of responses to urinary bladder distension in mice will also be examined.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK051413-07
Application #
6640075
Study Section
Special Emphasis Panel (ZRG1-UROL (01))
Program Officer
Mullins, Christopher V
Project Start
1997-07-25
Project End
2006-03-31
Budget Start
2003-06-01
Budget End
2004-03-31
Support Year
7
Fiscal Year
2003
Total Cost
$244,326
Indirect Cost
Name
University of Alabama Birmingham
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Ness, Timothy J; DeWitte, Cary; DeBerry, Jennifer J et al. (2018) Neonatal bladder inflammation alters the role of the central amygdala in hypersensitivity produced by Acute Footshock stress in adult female rats. Brain Res 1698:99-105
Ness, Timothy J; DeWitte, Cary; McNaught, Jamie et al. (2018) Spinal mechanisms of pudendal nerve stimulation-induced inhibition of bladder hypersensitivity in rats. Neurosci Lett 686:181-185
Clodfelder-Miller, Buffie J; Kanda, Hirosato; Gu, Jianguo G et al. (2018) Urothelial bladder afferent neurons in the rat are anatomically and neurochemically distinct from non-urothelial afferents. Brain Res 1689:45-53
Randich, Alan; DeWitte, Cary; DeBerry, Jennifer J et al. (2017) Lesions of the central amygdala and ventromedial medulla reduce bladder hypersensitivity produced by acute but not chronic foot shock. Brain Res 1675:1-7
Kanda, Hirosato; Clodfelder-Miller, Buffie J; Gu, Jianguo G et al. (2016) Electrophysiological properties of lumbosacral primary afferent neurons innervating urothelial and non-urothelial layers of mouse urinary bladder. Brain Res 1648:81-89
Deutsch, Georg; Deshpande, Hrishikesh; Frölich, Michael A et al. (2016) Bladder Distension Increases Blood Flow in Pain Related Brain Structures in Subjects with Interstitial Cystitis. J Urol 196:902-10
Goodin, Burel R; Ness, Timothy J; Robbins, Meredith T (2015) Oxytocin - a multifunctional analgesic for chronic deep tissue pain. Curr Pharm Des 21:906-13
Korbe, Samuel; Udoji, Esther N; Ness, Timothy J et al. (2015) Ultrasound-guided interventional procedures for chronic pain management. Pain Manag 5:465-82
Goodin, Burel R; Anderson, Austen J B; Freeman, Emily L et al. (2015) Intranasal Oxytocin Administration is Associated With Enhanced Endogenous Pain Inhibition and Reduced Negative Mood States. Clin J Pain 31:757-767
Hall, Jason D; DeWitte, Cary; Ness, Timothy J et al. (2015) Serotonin enhances urinary bladder nociceptive processing via a 5-HT3 receptor mechanism. Neurosci Lett 604:97-102

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