Chronic pelvic pain is a common symptom of many urologic and gastrointestinal disorders including interstitial cystitis and irritable bowel syndrome. Cross-sensitization among pelvic organs contributes to chronic pelvic pain of unknown etiology. Our long term goal is to elucidate the neural, neurohumoral and neuroimmune mechanisms underlying cross-sensitization in the pelvis and reveal its correlation with the occurrence of neurogenic inflammation and chronic pelvic pain. Recent studies demonstrated the role of sensory afferent pathways in pelvic organ cross-sensitization, however, our understanding of the underlying mechanisms is still rudimentary. We hypothesize that colonic inflammation alters the function of the urinary bladder due to sensitization of afferent sensory pathways in the spinal cord and dorsal root ganglia (DRG). We suggest that enhanced excitability of sensory neurons in the DRG and spinal cord induced by colonic inflammation alters the expression of pro-inflammatory neuropeptides as well as their release in the urinary bladder, leading to the development of neurogenic inflammation in the latter. Neuroanatomical, immunohistochemical, electrophysiological and neuropharmacological studies will be carried out to characterize the role of sensory neural pathways in cross-sensitization between the colon and urinary bladder.
The specific aims are designed to provide a comprehensive assessment of the proposed hypothesis.
Specific Aim 1 will determine whether colonic inflammation alters the excitability of bladder DRG neurons before and after desensitization of sensory afferents with resiniferatoxin (RTX). It will also address the effects of RTX treatment on the expression of TRPV1, CGRP and SP in thoracolumbar and lumbosacral DRG neurons.
Specific Aim 2 will focus on the role of capsaicin-sensitive C- and Adelta-fibers in the processing of nociceptive colonic afferent input to convergent and bladder neurons in the spinal cord.
Specific Aim 3 will test the hypothesis that desensitization of sensory fibers in the colon or urinary bladder prevents the development of a neurogenic bladder after experimentally induced colitis. We believe that uncovering these mechanisms will lead to the development of new therapeutic protocols that can be used to alleviate chronic pelvic pain in patients with genitourinary and gastrointestinal disorders.

Public Health Relevance

This project will study the neurohumoral mechanisms underlying the cross-sensitization among pelvic organs and reveal its correlation with the occurrence of neurogenic inflammation in the pelvis and chronic pelvic pain. Uncovering of these mechanisms will lead to the development of new therapeutic protocols that can be used to alleviate the chronic pelvic pain in patients with genitourinary and gastrointestinal disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Urologic and Kidney Development and Genitourinary Diseases Study Section (UKGD)
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Mullins, Christopher V
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University of Pennsylvania
Schools of Medicine
United States
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Hypolite, Joseph A; Chang, Shaohua; Wein, Alan J et al. (2015) Protein kinase C modulates frequency of micturition and non-voiding contractions in the urinary bladder via neuronal and myogenic mechanisms. BMC Urol 15:34
Malykhina, Anna; Hanno, Philip (2014) How are we going to make progress treating bladder pain syndrome? ICI-RS 2013. Neurourol Urodyn 33:625-9
Lei, Qi; Pan, Xiao-Qing; Chang, Shaohua et al. (2014) Response of the human detrusor to stretch is regulated by TREK-1, a two-pore-domain (K2P) mechano-gated potassium channel. J Physiol 592:3013-30
Moore, Kate H; Malykhina, Anna P (2014) What is the role of covert infection in detrusor overactivity, and other LUTD? ICI-RS 2013. Neurourol Urodyn 33:606-10
Pan, Xiao-Qing; Malykhina, Anna P (2014) Estrous cycle dependent fluctuations of regulatory neuropeptides in the lower urinary tract of female rats upon colon-bladder cross-sensitization. PLoS One 9:e94872
Malykhina, Anna P; Qin, Chao; Lei, Qi et al. (2013) Differential effects of intravesical resiniferatoxin on excitability of bladder spinal neurons upon colon-bladder cross-sensitization. Brain Res 1491:213-24
Lei, Qi; Pan, Xiao-Qing; Villamor, Antonio N et al. (2013) Lack of transient receptor potential vanilloid 1 channel modulates the development of neurogenic bladder dysfunction induced by cross-sensitization in afferent pathways. J Neuroinflammation 10:3
Malykhina, Anna P; Wyndaele, Jean-Jacques; Andersson, Karl-Erik et al. (2012) Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011. Neurourol Urodyn 31:352-8
Malykhina, Anna P; Lei, Qi; Erickson, Chris S et al. (2012) VEGF induces sensory and motor peripheral plasticity, alters bladder function, and promotes visceral sensitivity. BMC Physiol 12:15
Cory, Lori; Harvie, Heidi S; Northington, Gina et al. (2012) Association of neuropathic pain with bladder, bowel and catastrophizing symptoms in women with bladder pain syndrome. J Urol 187:503-7

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