The patients with chronic pelvic pain (CPP) experience unrelenting pain and urgency for voiding (hypereflexsive bladder) leading to poor quality of life. The NIDDK has calculated that CPP is responsible for 4,137,000 outpatient or clinic visits/year and about 90% of them are female. Recent study indicates that estimated medical cost for treating CPP exceeds $2 billion/year. The etiology of CPP is complex and difficult to understand. The pain arises due to dysfunction and/or inflammation of any of the pelvic structures including the urinary bladder (cystitis), hindgut (colitis, irritable bowel syndrome), uterus (fibroid and endometriosis) and prostrates (prostatitis) often overlaps to other pelvic and surrounding somatic structures. One of the risk factors for CPP is early episode of urinary tract infection (UTI). The intense painful stimulus and inflammation of the urinary bladder in the neonatal period may adversely affect the neurological development leading to CPP in adulthood. The underlying pathophysiology due to early-life inflammation could be entirely different from that of adults not subjected to any early-life episode and thus warrants further investigation. A systematic study will have significant clinical impact by implementing diagnostic biomarkers, effective prevention strategies and the development of therapeutic intervention. The inhibitory neurotransmitter g-amino butyric acid (GABA) plays a critical role in the pain modulation and lack of its function facilitates chronic pain. Very little is known about how the development of GABAergic system is affected due to neonatal noxious stimulus. A long- lasting pain condition due to early-life episodes may result in transcriptional and/or translational alteration in neurotransmitters and receptor expressions resulting altered neuronal functions, morphology and synaptic connections in adulthood. Although it is largely unknown how such changes in gene expressions induce chronic pain, recent evidence strongly suggests an important role for micro RNAs (miRNAs, small non-coding RNAs) in the cellular plasticity. We hypothesize that the long-lasting spinal sensitization following intense painful visceral stimulus in early-life involves miRNA-mediated posttranscriptional deregulation of developing GABAergic pathway in neonates. The loss of GABAergic tone could be due to (1) lack of GABA synthesis (downregulation of GABA synthesizing enzymes gad1 and/or gad2), (2) downregulation of GABAA receptor subunits (and (3) downregulation of K+, Cl- co- transporter 2 (KCC2) and vesicular GABA transporter (VGAT) in the spinal cord. The proposed study is the first systematic investigation of intrinsic neuromolecular mechanism involved in altered GABAergic tone contributing to CPP in adulthood.

Public Health Relevance

It has been estimated that about 1.2 million women and 82,000 men in the United States suffer from interstitial cystitis (IC)/painful bladder syndrome (PBS) [1]. The risk factor for IC/PBS is predominantly higher in female gender. The possible risk factors that have been proposed include heredity and previous episode of urinary tract infection [2]. Anecdotal reports suggest that some patients experience the onset of IC/PBS symptoms after an episode of acute bacterial cystitis. However, current research does not support bacterial infection as a risk factor for the condition, although it remains possible that infection serves asa trigger in some patients [1, 2]. The importance chronic pelvic pain (CPP) has been recognized by NIDDK very recently leading to a multi- disciplinary approach (MAPP, :// to understand the epidemiology of disease, phenotyping of the urological and non-urological symptoms, neuroimaging, identification of biomarkers of disease and characterizations of organ cross-talk and pain signaling pathways. IC/PBS has a significant impact on individual patients and their quality of life. Patients with IC experience unrelenting pain and urgency for voiding. Because of the recurrent pain and frequency, many patients with IC/PBS are unable to focus and fulfill their work or family obligations. Often intense pain interrupts sleep, leading to fatigue and depression [3]. The NIDDK has calculated that IC/PBS was responsible for at least 4,137,000 outpatient physician or clinic visits in 2000 and an outlay of $65.9 million, excluding missed work and lost productivity [4]. Estimates of medical costs plus lost productivity were $428 million in 1987 [5]. A large proportion of patient population develops overlapping pelvic pain, which creates a real challenge to manage the pain clinically. Our long-term goal is to have a thorough understanding of neuromolecular basis of CPP, especially in that subset of patients who are more prone to this syndrome. Our proposed study will be the first systematic evaluation integrating physiological and molecular approaches to investigate the underlying mechanism of long-term plasticity of the spinal neurons involved in neonatal cystitis-induced chronic bladder pain as well as cross-organ sensitization, a pathological cause for overlapping pelvic pain. The identification of specific miRNAs and their target genes will have a significant impact on the development of therapeutic targets and/or biomarkers, which will aid in early detection, diagnosis and for developing an effective pain management strategy. Reference: 1. Clemens JQ, Joyce GF, Wise M, Payne CK. Interstitial cystitis and painful bladder syndrome. In: Litwin MS, Saigal CS, editors. Urologic Diseases in America. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office;2007. NIH Publication No. 07-5512:125-154. 2. Moldwin RM, Sant GR. Interstitial cystitis: a pathophysiology and treatment update. Clin Obstet Gynecol. 2002;45:259-72. 3. Rabin C, O'Leary A, Neighbors C, Whitmore KE. Pain and depression experienced by women with interstitial cystitis. Women &Health. 2000;31(4):67-81. 4. Litwin MS, Saigal CS. Introduction. In: Litwin MS, Saigal CS, editors. Urologic Diseases in America. US Department of Health and Human Services, Public Health Service, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases. Washington, DC: US Government Printing Office, 2007. NIH Publication No. 07-5512:3-7. 5. Held PJ, Hanno PM, Wein AJ, Epidemiology of interstitial cystitis: 2. In: Hanno PM, Staskin DR, Krane RJ, et al., editors. Interstitial Cystitis. New York: Springer-Verlag;1990. pp. 29-48.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (UGPP)
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Mullins, Christopher V
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Medical College of Wisconsin
Internal Medicine/Medicine
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United States
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