Bladder Hypersensitivity Research Articles

Tadalafil Effect on Metabolic Syndrome-Associated Bladder Alterations: An Experimental Study in a Rabbit Model

Metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) are often associated. Bladder detrusor hyper-contractility-a major LUTS determinant-is characterized by increased Ras homolog gene family, member A/Rho-associated protein kinase (RhoA/ROCK) signaling, which is often upregulated in MetS. This study investigated the effects of tadalafil dosing on RhoA/ROCK signaling in bladder, in a rabbit model of high-fat diet (HFD)-induced MetS. Adult male rabbits feeding a HFD for 12 weeks. A subset of HFD animals was treated with tadalafil (2 mg/kg/day, 1 week: the last of the 12 weeks) and compared with HFD and control (feeding a regular diet) rabbits. In vitro contractility studies to evaluate the relaxant effect of the selective ROCK inhibitor, Y-27632, in carbachol precontracted bladder strips. Evaluation of RhoA activation by its membrane translocation. Immunohistochemistry for ROCK expression has been performed to evaluate ROCK expression in bladder from the different experimental groups. mRNA expression of inflammation, pro-fibrotic markers by quantitative RT-PCR has been performed to evaluate the effect of tadalafil on MetS-induced inflammation and fibrosis within the bladder. The in vitro effect of tadalafil on RhoA/ROCK signaling in bladder smooth muscle cells was evaluated by using chemotaxis assay. Bladder strips from HFD rabbits showed hyper-responsiveness to Y-27632, indicating RhoA/ROCK overactivity in HFD bladder compared with matched controls. Accordingly, the fraction of activated (translocated to the membrane) RhoA as well as ROCK expression are increased in HFD bladder. Tadalafil dosing normalized HFD-induced bladder hypersensitivity to Y-27632, by reducing RhoA membrane translocation and ROCK overexpression. Tadalafil dosing reduced mRNA expression of inflammatory, pro-fibrotic, and hypoxia markers. A direct inhibitory effect of tadalafil on RhoA/ROCK signaling in bladder smooth muscle cell was demonstrated by using chemotaxis assay. Pre-treatment with tadalafil inhibited both basal and PDGF-induced migration of bladder smooth muscle cells. Tadalafil dosing reduced RhoA/ROCK signaling and smooth muscle overactivity in an animal model of MetS-associated bladder alterations. Our findings suggest a novel mechanism of action of tadalafil in alleviating LUTS in MetS patients.

Hypersensitive bladder: a solution to confused terminology and ignorance concerning interstitial cystitis.

Taxonomy or nomenclature concerning interstitial cystitis and its related symptom syndromes is in a state of confusion. After analyzing the reasons for confusion in regard to three components (disease name, symptoms, Hunner's lesion), I would like to propose a new term, "hypersensitive bladder", taking after overactive bladder, as a solution. Hypersensitive bladder symptoms are defined as "increased bladder sensation, usually associated with urinary frequency and nocturia, with or without bladder pain." The proposal of hypersensitive bladder is based on: (i) it does not appear a symptom syndrome, but a disease by ending with an organ name, "bladder"; (ii) it does not contain confusable symptom terms (pain and urgency), but indicates irritative symptoms including pain and urgency; and (iii) it suggests pathophysiological hyperactivity of sensory nerves. Interstitial cystitis is defined by three requirements: (i) hypersensitive bladder symptoms; (ii) bladder pathology; and (iii) no other diseases, where bladder pathology should be clearly stated either as Hunner's lesion or glomerulations after hydrodistention. Hypersensitive bladder can be used for the condition with hypersensitive bladder symptoms, but no obvious disease explaining hypersensitive bladder symptoms identified. Interstitial cystitis is a representative disease causing hypersensitive bladder symptoms, most typically with pain, but might be painless and indistinguishable from overactive bladder. Introducing hypersensitive bladder as a counter concept of overactive bladder into bladder dysfunction taxonomy will facilitate clinical practice and research progress, and attract considerable attention from the medical world.

Interstitial cystitis and the painful bladder: A brief history of nomenclature, definitions and criteria

"Practically every author writing on this subject has suggested a new name which only adds to the confusion and multiplication" (Kretschmer H, 1922). Despite multiple names and many definitions and classifications over the past two centuries, the medical world is no closer to discovering the cause or causes of this enigmatic bladder disorder, currently known as interstitial cystitis, bladder pain syndrome or painful bladder syndrome and hypersensitive bladder. International consensus on nomenclature, definitions and diagnosis is now essential to ensure that studies are carried out on the same basis, thereby generating meaningful data that can be relied on for further use. In our electronic age, multiple names and definitions cause confusion for researchers, clinicians and patients, even leading to the patient's diagnosis being unrecognized by authorities, resulting in refusal to reimburse treatment or provide social benefits. As the key to the puzzle lies in the patients, with all their symptoms and comorbidities, and as patients are directly affected by changes in nomenclature and definitions, patient organization representatives should be given every opportunity to participate in discussions on guidelines, taxonomy, definitions and terminology.

Potential urine and serum biomarkers for patients with bladder pain syndrome/interstitial cystitis.

There is a lack of consensus on the pathophysiology of bladder pain syndrome/interstitial cystitis. The chronic pain symptoms of bladder pain syndrome/interstitial cystitis refractory to local treatment could be a result of central nervous system sensitization and persisting abnormalities in the bladder wall, which activate the afferent sensory system. Evidence also shows that bladder pain syndrome/interstitial cystitis is a heterogeneous syndrome and that the two subtypes, the ulcerative (classic) and non-ulcerative types, represent different disease entities. There is a need for non-invasive markers for the differential diagnoses of the subtypes of bladder pain syndrome/interstitial cystitis, and between bladder pain syndrome/interstitial cystitis and bladder sensory disorders, such as hypersensitive bladder syndrome or overactive bladder. Bladder pain syndrome/interstitial cystitis, but not overactive bladder, involves an aberrant differentiation program in the bladder urothelium that leads to altered synthesis of several proteoglycans, cell adhesion and tight junction proteins, and bacterial defense molecules. These findings have led to the rationale for identifying urinary biomarkers to detect bladder pain syndrome/interstitial cystitis in patients with frequency urgency syndrome. Recently, the markers that have been the focus of the most research are antiproliferative factor, epidermal growth factor, heparin-binding epidermal growth factor, glycosaminoglycans and bladder nitric oxide. In addition, inflammatory proteins in the urine and serum play important roles in the pathogenesis of bladder pain syndrome/interstitial cystitis. The urinary proteome is an easily accessible source of biomarkers for differentiation between inflammatory bladder disorders. Analysis of multiple urinary proteins and serum cytokines could provide a diagnostic basis for bladder pain syndrome/interstitial cystitis, and could be a tool for the differential diagnosis of bladder pain syndrome/interstitial cystitis and other sensory bladder disorders.

PD9-01 THERAPEUTIC EFFECT OF ANTISENSE OLOGONUCLEOTIDE (OND) TARGETING NERVE GROWTH FACTOR (NGF) ON BLADDER HYPESENSITIVITY IN RAT WITH EXPERIMENTAL COLITIS

You have accessJournal of UrologyInfections/Inflammation of the Genitourinary Tract: Interstitial Cystitis1 Apr 2014PD9-01 THERAPEUTIC EFFECT OF ANTISENSE OLOGONUCLEOTIDE (OND) TARGETING NERVE GROWTH FACTOR (NGF) ON BLADDER HYPESENSITIVITY IN RAT WITH EXPERIMENTAL COLITIS Naoki Kawamorita, Satoru Yoshikawa, Yoichi Arai, Pradeep Tyagi, Michael Chancellor, and Naoki Yoshimura Naoki KawamoritaNaoki Kawamorita More articles by this author , Satoru YoshikawaSatoru Yoshikawa More articles by this author , Yoichi AraiYoichi Arai More articles by this author , Pradeep TyagiPradeep Tyagi More articles by this author , Michael ChancellorMichael Chancellor More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.783AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Pelvic organ “cross sensitization” seems to contribute to overlapping symptoms in patients with chronic pelvic pain syndrome (CPPS) including bladder pain syndrome/interstitial cystitis (BPS/IC). However, it is not known whether NGF overexpression in the bladder is involved in this cross sensitization mechanism. Therefore, we investigated whether local instillation of liposome-OND conjugates (L-OND) targeting NGF overexpression in the bladder can suppress bladder hypersensitivity in a rat model of experimental colitis. METHODS Five groups of female SD rats were used; (a) control (no treatment), (b) colitis-OND (intracolonic 2,4,6,trinitrobenzen sulfonic acid [TNBS] enema & intravesical L-OND), (c) colitis-saline (TNBS & intravesical saline), (d) sham-OND (L-OND was given without colitis) and (e) sham-saline (saline was given without colitis). A day before evoking TNBS colitis, either L-OND or saline was instilled to the bladder. (1) Behavior testing: Resiniferatoxin (0.3µM, 0.3 ml) was administered into the bladder for 1 min to evaluate nociceptive behaviors such as licking (lower abdominal licking) and freezing (motionless head-turning) for 15 min. (2) Cystometry: Saline followed by 0.1% acetic acid (AA) were continuously infused to evaluate changes in intracontraction intervals (ICIs) in conscious rats. (3) Molecular analysis: Harvested bladders were divided to mucosal and detrusor layers to measure the mRNA and protein expression of NGF by qPCR and ELISA, respectively. RESULTS (1) In the colitis-saline group, the score of freezing behavior, which represents bladder pain sensation, was significantly higher than that of other groups including the colitis-OND group. (2) The reduction rate of ICI after AA instillation in the colitis-saline group was approximately 40% in contrast to 10% in the colitis-OND group. (3) The mRNA and protein expression of NGF in the mucosa was significantly higher in the colitis-saline group compared to the colitis-OND group. CONCLUSIONS These results indicate that intravesical treatment of NGF antisense with liposome, which suppressed mucosal NGF overexpression, reduced colitis-induced bladder hypersensitivity evidenced by increased bladder pain behavior (freezing) and AA-induced bladder overactivity. Thus, the intravesical NGF antisense treatment could be effective for hypersensitive bladder symptoms in CPPS including BPS/IC, in which the cross-sensitization mechanism contributes to overlapping symptoms from different pelvic organs. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e211 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Naoki Kawamorita More articles by this author Satoru Yoshikawa More articles by this author Yoichi Arai More articles by this author Pradeep Tyagi More articles by this author Michael Chancellor More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

MP1-03 HERPES SIMPLEX VIRUS (HSV) VECTOR-MEDIATED GENE DELIVERY OF PROTEIN PHOSPHATASE 1α REDUCES BLADDER OVERACTIVITY AND NOCICEPTION IN RATS

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Basic Research I1 Apr 2014MP1-03 HERPES SIMPLEX VIRUS (HSV) VECTOR-MEDIATED GENE DELIVERY OF PROTEIN PHOSPHATASE 1α REDUCES BLADDER OVERACTIVITY AND NOCICEPTION IN RATS Tsuyoshi Majima, Naoki Kawamorita, Hiroki Okada, Yasuhito Funahashi, Momokazu Gotoh, William Goins, Joseph Glorioso, Justus Cohen, Bonnie Hall, Asaff Harel, and Naoki Yoshimura Tsuyoshi MajimaTsuyoshi Majima More articles by this author , Naoki KawamoritaNaoki Kawamorita More articles by this author , Hiroki OkadaHiroki Okada More articles by this author , Yasuhito FunahashiYasuhito Funahashi More articles by this author , Momokazu GotohMomokazu Gotoh More articles by this author , William GoinsWilliam Goins More articles by this author , Joseph GloriosoJoseph Glorioso More articles by this author , Justus CohenJustus Cohen More articles by this author , Bonnie HallBonnie Hall More articles by this author , Asaff HarelAsaff Harel More articles by this author , and Naoki YoshimuraNaoki Yoshimura More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.101AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Increased afferent excitability has been proposed as an important pathophysiological basis of overactive bladder (OAB) and hypersensitive bladder disorders such as interstitial cystitis/bladder pain syndrome (IC/BPS). It has also been reported that transient receptor potential vanilloid-1 (TRPV1) receptors predominantly expressed in C-fiber afferent pathways greatly contribute to afferent sensitization in these disease conditions. We recently found Protein Phosphatase 1α (PP1α) as a modulator of TRPV1 receptor activity using an HSV vector cDNA library screen method to identify genes that inhibit TRPV1 activation, and showed that HSV vector-mediated PP1α expression led to the reduction in capsaicin-induced thermal hyperalgesia. Therefore, this led us to investigate the effect of HSV vectors-mediated gene delivery of PP1α on TRPV1-mediated bladder overactivity and pain-related behavior in rats. METHODS Replication-deficient HSV vectors encoding PP1α or green fluorescent protein (GFP) as control were injected into the bladder wall of adult female Sprague-Dawley rats. Cystometry (CMG) under urethane anesthesia was performed 1 week after viral injection to evaluate bladder overactivity induced by resiniferatoxin (RTX, a TRPV1 agonist). RTX-induced nociceptive behavior such as licking (lower abdominal licking) and freezing (motionless head-turning) was observed 2 weeks after viral injection. Using immunohistochemistry, GFP expression in L6/S1 DRG and the bladder as well as c-Fos positive cells in the L6 spinal cord dorsal horn were evaluated. RESULTS GFP expression was seen in L6/S1 DRG sections. In CMG, the PP1α group showed a significantly (p<0.05) smaller reduction (46.5±1.7%) in intercontraction intervals after RTX infusion than the GFP group (65.7±3.8%). The number of RTX-induced freezing behavior, which is correlated with bladder pain sensation, was significantly (p<0.001) decreased in PP1α vs. GFP groups. The number of c-Fos positive cells in the L6 spinal dorsal horn was significantly (p<0.01) smaller in PP1α vs. GFP rats (24±4 vs. 59±6 cells per section). CONCLUSIONS These results indicate that HSV vectors injected into the bladder wall are transported to lumbosacral DRGs that contain bladder afferent neurons, and that PP1α gene delivery in the bladder is effective in suppressing TRPV1-mediated bladder overactivity and pain behavior. Thus, HSV-mediated PP1α gene therapy could be effective for the treatment of OAB and/or hypersensitive bladder disorders such as IC/BPS. © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e1-e2 Peer Review Report Advertisement Copyright & Permissions© 2014MetricsAuthor Information Tsuyoshi Majima More articles by this author Naoki Kawamorita More articles by this author Hiroki Okada More articles by this author Yasuhito Funahashi More articles by this author Momokazu Gotoh More articles by this author William Goins More articles by this author Joseph Glorioso More articles by this author Justus Cohen More articles by this author Bonnie Hall More articles by this author Asaff Harel More articles by this author Naoki Yoshimura More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Interstitial cystitis in urology clinic: current status and problems

We examined the complications in the diagnosis and treatment of interstitial cystitis in daily clinical practice. The study included 82 patients who were suspected of having interstitial cystitis at our hospital from March 2002 to April 2013. All hydrodistention procedures were performed with the aid of an anesthesiologist, as recommended by the Ministry of Health, Labour, and Welfare since April 2010. Of the 82, 20 patients were male and 62 were female, (mean age at diagnosis 53 years.) Six of the suspected cases did not have interstitial cystitis. Of the 67 patients diagnosed with interstitial cystitis during hydrodistention, 29 (43%) did not experience pain. The time taken to diagnose these asymptomatic patients was longer than that taken for those who experienced pain. Twenty-eight patients (42%) discontinued treatment because it was ineffective. Interstitial cystitis has been widely recognized, but general physicians are unable to provide a diagnosis and suggest aggressive treatment because of difficulty associated in the treatment and diagnosis. To resolve these issues, physicians should be keep in mind that interstitial cystitis involves a hypersensitive bladder, and that some patients may not experience pain. Further, knowledge about Hunner's ulcer is essential. We believe that the most important points are improving health insurance about facility criteria of hydrodistention, and evaluating behavioral modification and dietary manipulation.

Urine alkalization improves the problems of pain and sleep in hypersensitive bladder syndrome

To investigate the efficacy of urine alkalization therapy using citrates in patients with hypersensitive bladder syndrome. A total of 76 patients with urinary frequency were assessed for their symptoms using a 2-day voiding diary as well as the urine pH at each voiding during the screening period. Their symptoms were also assessed by pain score, King's health questionnaire, and O'Leary-Sant symptom and problem index scores. Finally, 50 patients were evaluated for changes in symptoms after oral treatment with citrates for 2-4 weeks after the screening period. After the treatment, significant increases in the urine pH (from 5.8 ± 0.4 to 6.3 ± 0.4; increment of 0.5 ± 0.4; P < 0.01), and significant decreases in the number of micturitions per day (from 14.5 ± 6.5 to 13.5 ± 5.9; P = 0.02) and the number of episodes of pain/discomfort per day (from 7.8 ± 6.8 to 6.1 ± 7.1; P = 0.02) were observed. In the King's health questionnaire, the sleep/energy domain score was significantly improved (from 60.0 ± 25.0 to 50.3 ± 29.6; P < 0.01). In a subgroup analysis based on urine pH (urine pH <6.2 and ≥6.2), significant improvements in the voiding symptoms, the sleep/energy domain score and the O'Leary-Sant problem index were observed in the group with urine pH of ≥6.2. There were statistically significant differences between the subgroups in the volume per voiding, maximum volume per voiding and the problem index. In addition, the subgroup, in which patients had pain in the screening period, showed statistically significant improvements in the number of micturitions per day, episodes of pain/discomfort per day, the sleep/energy domain score and the problem index. Urine alkalization therapy is likely to be effective in the treatment for hypersensitive bladder syndrome.

An Endogenous Pain Control System is Altered in Subjects with Interstitial Cystitis

Multiple studies have demonstrated that in healthy subjects, painful stimuli applied to one part of the body inhibit pain sensation in other parts of the body, a phenomenon referred to as conditioned pain modulation. Conditioned pain modulation is related to the presence of endogenous pain control systems. Studies have demonstrated deficits in conditioned pain modulation associated inhibition in many but not all chronic pain disorders. In this study we determine whether conditioned pain modulation is altered in subjects with interstitial cystitis/bladder pain syndrome. Female subjects with and without the diagnosis of interstitial cystitis/bladder pain syndrome were studied psychophysically using quantitative cutaneous thermal, forearm ischemia and ice water immersion tests. Conditioned pain modulation was assessed by quantifying the effects of immersion of the hand in ice water (conditioning stimulus) on threshold and tolerance of cutaneous heat pain (test stimulus) applied to the contralateral lower extremity. The conditioned pain modulation responses of the subjects with interstitial cystitis/bladder pain syndrome were statistically different from those of healthy control subjects for cutaneous thermal threshold and tolerance measures. Healthy control subjects demonstrated statistically significant increases in thermal pain tolerance whereas subjects with the diagnosis of interstitial cystitis/bladder pain syndrome demonstrated statistically significant reductions in thermal pain tolerance. An endogenous pain inhibitory system normally observed with conditioned pain modulation was altered in subjects with interstitial cystitis/bladder pain syndrome. This finding identifies interstitial cystitis/bladder pain syndrome as similar to several other chronic pain disorders such as fibromyalgia and irritable bowel syndrome, and suggests that a deficit in endogenous pain inhibitory systems may contribute to such chronic pain disorders.

Bladder hypersensitivity and transcriptional regulation of potassium channel subunit mRNA expression in mice with cystitis

Hyperexcitability in bladder primary afferents contributes to bladder overactivity and pain in pathological urological conditions. Target-derived growth factors can alter primary afferent expression of membrane-bound ion channels that regulate neuronal excitability, such as voltage-gated potassium (Kv) channels. Several Kv channels are expressed in primary afferent neurons and contain a binding site for repressor element-1-silencing transcription factor (REST). Growth factor-mediated, REST-induced, long-lasting downregulation of Kv channels may provide a mechanism through which persistent changes in bladder afferent sensitivity can occur.

Hypersensitive bladder: Towards clear taxonomy surrounding interstitial cystitis

Hypersensitive bladder: Towards clear taxonomy surrounding interstitial cystitis

An evidence‐based approach to urodynamic testing

for this article http://dx.doi.org/10.1016/j.juro.2014.07.074 available at http://jurology.com/ Editorial Comment: This is a well constructed article that is almost a point/counterpoint, since the answer seems to be, maybe, but what can we use it for? The article very nicely reviews published studies discussing the pros and cons of NGF as a potential biomarker. The bottom line is that while the evidence for increased urinary NGF in OAB appears convincing, many questions remain about specificity, sensitivity, cost and time effectiveness. NGF urinary levels have been reported to be increased in bladder pain syndrome, idiopathic and neurogenic detrusor overactivity, bladder hypersensitivity and bladder outflow obstruction. Although increased levels do appear to decrease after successful treatments, at least in some reports regarding antimuscarinic and botulinum toxin therapy, one has to wonder if there is any other real practical use, other than one facet of monitoring response to treatment, since the diagnosis of overactive bladder relies on symptoms. If someone has urgency and frequency, with or without urgency incontinence, that individual would appear to fit in the category of the overactive bladder symptom syndrome whether or not urinary NGF levels are elevated. The true value of studies regarding the physiology of NGF may be the information they provide regarding various signaling mechanisms involved in the sensory or motor changes that occur in bladder function in various types of pathologies. Alan J. Wein, MD, PhD (hon) Suggested Reading Lee SR, Hong CH, Choi YD et al: Increased urinary nerve growth factor as a predictor of persistent detrusor overactivity after bladder outlet obstruction relief in a rat model. J Urol 2010; 183: 2440. Giannantoni A, Di Stasi SM, Nardicchi V et al: Botulinum-A toxin injections into the detrusor muscle decrease nerve growth factor bladder tissue levels in patients with neurogenic detrusor overactivity. J Urol 2006; 175: 2341. Antunes-Lopes T, Pinto R, Barros SC et al: Urinary neurotrophic factors in healthy individuals and patients with overactive bladder. J Urol 2013; 189: 359. Liu HT and Kuo HC: Urinary nerve growth factor level could be a potential biomarker for diagnosis of overactive bladder. J Urol 2008; 179: 2270.

Early-in-life bladder inflammation alters U50,488H but not morphine-induced inhibition of visceromotor responses to urinary bladder distension

Previous research has suggested that early-in-life (EIL) exposure to bladder inflammation impairs the function of endogenous opioid inhibitory system(s) and may contribute to the development of chronic bladder pain. This study examined how acute adult and/or prior EIL exposure to bladder inflammation altered the inhibitory effects of systemic κ- and μ-opioid agonists on the visceromotor reflex (VMR) to urinary bladder distension (UBD). Female rats were exposed intravesically EIL (P14–P16) to either the inflammatory agent zymosan or anesthesia-alone, and then rechallenged as adults (12–17 weeks) with either anesthesia-alone or zymosan. The VMR to 60mmHg UBD was measured after cumulative intravenous (i.v.) administration of 1mg/kg and 4mg/kg of either the κ-opioid agonist U50,488H or the μ-opioid agonist morphine. Morphine produced dose-dependent inhibition of the VMR to UBD in all groups, and U50,488H produced dose-dependent inhibition of the VMR to UBD in all but one group. Animals that received bladder inflammation both EIL and as adults showed significantly augmented VMRs to UBD (>100% baseline values) following 1mg/kg of U50,488H and diminished inhibition of VMRs following 4mg/kg of U50,488H when compared with other groups. In contrast, neither EIL nor adult bladder inflammation markedly altered the inhibition of the VMR to UBD produced by either 1 or 4mg/kg of i.v. morphine. These data suggest EIL and adult exposure to bladder inflammation selectively decreases the inhibitory effects of κ-opioids and thereby may enhance bladder hypersensitivity in patients with painful bladder syndromes.

Urge Perception Index of Bladder Hypersensitivity

By analyzing bladder diaries with patient self-reported urinary perception grades, we developed the urge perception index, a quantitative measure of bladder hypersensitivity. We evaluated the impact of the urge perception index on the definition of overactive bladder severity. We retrospectively evaluated the records of 69 female patients who visited our outpatient clinic with the complaint of storage symptoms. Patients were asked to complete the overactive bladder symptom score and a 3-day bladder diary with self-reported grading of urinary perception on a range of 1 to 5 per void. Overactive bladder was diagnosed in 43 patients and nonoveractive bladder was diagnosed in 26. The urge perception index was defined as voided volume divided by the urinary perception grade at each void. We analyzed 1,578 reported voids. According to the urinary perception grade, urge perception index values for overactive bladder were significantly lower than those for nonoveractive bladder (grades 1 to 4 p <0.001). The average ± SD urge perception index in 3-day bladder diaries was lower in overactive than in nonoveractive bladder cases (55 ± 28 vs 133 ± 73, p <0.0001). The most severe (lowest) single urge perception index value during the 3 days was significantly lower in patients with overactive than with nonoveractive bladder (mean 20 ± 12 vs 62 ± 40, p <0.0001). There were negative linear correlations of the urge perception index with total overactive bladder symptom scores (r = -0.598, p <0.0001) and with an urgency symptom score (r = -0.557, p <0.0001). The urge perception index, an integrated parameter of patient reported bladder perception and voided volume, could be promising to quantify the severity of overactive bladder or bladder hypersensitivity by bladder diary analysis.

Early in Life Bladder Inflammation Alters Opioid Peptide Content in the Spinal Cord and Bladder of Adult Female Rats

Previous research suggests that a failure of opioid inhibition may contribute to chronic bladder pain. We determined how acute adult and/or prior early in life exposure to bladder inflammation alters the adult content of endogenous opioid peptides in the bladder, spinal cord and blood. Inflammation was induced by intravesical administration of zymosan. Female Sprague-Dawley® rats were exposed to anesthesia only or zymosan early in life (postnatal days 14 to 16) and anesthesia only or zymosan as adults (ages 12 to 17 weeks). Thoracolumbar and lumbosacral segments of the spinal cord, and blood and bladders were collected 24 hours after adult treatment. Opioid peptide content was measured using enzyme-linked immunosorbent assay. Early in life bladder inflammation alone produced a chronic increase in dynorphin A (1-17) in the lumbosacral spinal cord. When early in life inflammation was followed by adult re-inflammation, spinal cord dynorphin remained unchanged but bladder dynorphin was decreased. In addition, early in life inflammation combined with adult bladder inflammation decreased endomorphin-2 content in the thoracolumbar spinal cord. Neither early in life nor adult bladder inflammation affected thoracolumbar dynorphin, serum dynorphin, lumbosacral endomorphin-2 or plasma β-endorphin. Several opioid peptides were measured using enzyme-linked immunosorbent assay following early in life and adult bladder inflammation. The changes observed are consistent with the view that early in life bladder inflammation alone can chronically alter spinal cord peptide content. When coupled with adult re-inflammation, these changes could set the neurochemical stage to support bladder hypersensitivity.

Voiding Dysfunction Associated with Pudendal Nerve Entrapment

Pudendal nerve entrapment (Alcock canal syndrome) is an uncommon source of chronic pelvic pain, in which the pudendal nerve is entrapped or compressed. Pain is located in the perineal, genital and perianal areas and is worsened by sitting. By simple entrapment of the PN without neurogenic damages, pain is usually isolated. In neurogenic damages to the PN, genito-anal numbness, fecal and/or urinary incontinence can occurred. PNE can be caused by obstetric traumas, scarring due to genitoanal surgeries (prolaps procedures!), accidents and surgical mishaps. Diagnosis is based on anamnesis, clinical examination including vaginal or rectal palpation of the pelvic nerves with selective nerve blockade. Pudendal pain non systematic mean PNE since other neuropathies may induce pudendal pain. So sacral radiculopathies (sacral nerves roots S#2-4) are underestimated etiologies frequently responsible for pudendal pain with irradiation in sacral dermatomes, bladder hypersensitivity or in neurogenic lesions, bladder retention.

Botulinum toxin injection for lower urinary tract dysfunction

Botulinum toxin has been recently accepted as a novel treatment for lower urinary tract dysfunctions refractory to conventional treatment. Review of the clinical trials in recent years, botulinum toxin type A has been widely used in the urethra or urinary bladder to treat voiding dysfunction due to detrusor sphincter dyssynergia, incontinence due to neurogenic or idiopathic detrusor overactivity, sensory disorders such as bladder hypersensitivity, overactive bladder, and interstitial cystitis/painful bladder syndrome. Intravesical botulinum toxin type A injection is effective in treatment of urinary incontinence due to detrusor overactivity in men and women, as well as in children. Currently botulinum toxin type A has also been applied to treat lower urinary tract symptoms due to benign prostatic hyperplasia in patients not suitable for surgery. This article reviewed the recent advances of botulinum toxin type A on lower urinary tract dysfunction.

Is There Any Role for Urodynamic Study in Children with High-grade Vesicoureteral Reflux?

To determine the clinical symptoms and urodynamic characteristics among children with primary high-grade vesicoureteral reflux (VUR). We prospectively studied clinical symptoms and urodynamic parameters in 147 consecutive patients ≤ 12 years old with idiopathic high-grade VUR referred to our hospital. Of 147 patients with high-grade VUR, 139 cases with mean age of 5.3 years met our inclusion criteria (88.5% females, 11.5% males). The most common symptom was recurrent urinary tract infection (57%) and urgency (59%) followed by enuresis (31.6%) and frequency (26.6%). Normal urodynamic findings were observed in 23% of patients. Overactive bladder (74%), high-end filling pressure (72.7%), low-compliance bladder (56%), and low bladder capacity (51%) were the most common urodynamic reports in this study. Other urodynamic findings were underactive bladder (1.5%), hypersensitive bladder (1.5%), hyposensitive bladder (3%), and high capacity bladder (2.2%). Proper management of VUR is very important because of its harmful potential effects on kidney function in children. With regard to the issue that most children with grade III and higher VUR had overactive bladder, high-end filling pressure, and other urodynamic disorders in their urodynamic study, it seems that these urodynamic disorders could be the basic cause of reflux.

Time‐dependent changes in bladder function and plantar sensitivity in a rat model of fibromyalgia syndrome induced by hydrochloric acid injection into the gluteus

To examine the correlation between muscular pain and bladder hypersensitivity in order to clarify the pathogenesis of comorbidity of bladder pain syndrome/interstitial cystitis with other chronic pain conditions such as fibromyalgia syndrome (FMS). Under isoflurane anaesthesia, 0.2 mL of hydrochloric acid (HCl) solution (pH 4.0) was injected into the bilateral gluteus muscles of female Sprague-Dawley rats to produce an FMS model, as the gluteus is one of the specific tender points in patients with FMS. Control rats received saline injection (0.2 mL). The mechanical sensitivity of the plantar was evaluated using the mean number of bilateral hindlimb withdrawals in response to tactile stimulation with a 2.0-g von Frey filament at 1, 2 and 3 weeks after the HCl injection. In a separate rat group, cystometry was performed with the rats awake during saline infusion (0.06 mL/min) into the bladder before and after 1% lidocaine injection (0.2 mL) into the bilateral gluteus 1, 2 and 3 weeks after the HCl injection. The mean number of hindlimb withdrawals was significantly higher in FMS rats than in controls at 1 and 2 weeks. Using cystometry, we found that the intercontraction interval (ICI) and voided volume (VV) were significantly lower in FMS rats than in controls at 1 and 2 weeks. In addition, the voiding threshold pressure, ICI and VV were significantly higher after lidocaine injection in FMS rats, but not in controls, at 1 and 2 weeks. HCl injection (pH 4.0) into the gluteus can induce plantar hypersensitivity and urinary frequency for up to 2 weeks after the injection, suggesting that somatic (gluteus)-to-visceral (bladder) cross-sensitization might underlie bladder hypersensitivity in patients with FMS. Moreover, intervention at specific tender points outside the bladder could be effective in treating urinary frequency because lidocaine injection into the gluteus normalized bladder function in FMS rats for up to 2 weeks.

Colitis-induced brain-derived neurotrophic factor in rat dorsal root ganglia mediates calcitonin gene-related peptide expression and bladder hyperactivity

Background/Aims: Neurotrophins play important roles in mediating and modulating sensory plasticity in normal and diseased states, and may also have roles in colitis-induced bladder hypersensitivity. The aims of this study are to examine the pathways leading to the expression of brain-derived neurotrophic factor (BDNF) in dorsal root ganglia (DRG) during colitis, and to examine the role of BDNF in calcitonin gene-related peptide (CGRP) expression in DRG. We also examined the role of BDNF in colitis-elicited increases in bladder voiding frequency.