Clinical impact of overactive bladder

Overactive bladder (OAB) is a medical condition with the symptoms of urinary frequency and urgency, with or without urge incontinence. Traditionally, epidemiologic studies have focused on the symptom of incontinence, and therefore the prevalence and clinical impact have been grossly underestimated. Recently, several population-based studies have been conducted that have provided insight into the true magnitude of OAB. This article will review the latest data on the prevalence of OAB and discuss the impact of the condition on quality of life. Furthermore, it will examine some of the comorbidities associated with OAB and look at the potential economic impact of OAB.     

Association of overactive bladder and stress urinary incontinence in rats with pudendal nerve ligation injury

Approximately one-third of patients with stress urinary incontinence (SUI) also suffer from urgency incontinence, which is one of the major symptoms of overactive bladder (OAB) syndrome. Pudendal nerve injury has been recognized as a possible cause for both SUI and OAB. Therefore, we investigated the effects of pudendal nerve ligation (PNL) on bladder function and urinary continence in female Sprague-Dawley rats. Conscious cystometry with or without capsaicin pretreatment (125 mg/kg sc), leak point pressures (LPPs), contractile responses of bladder muscle strips to carbachol or phenylephrine, and levels of nerve growth factor (NGF) protein and mRNA in the bladder were compared in sham and PNL rats 4 wk after the injury. Urinary frequency detected by a reduction in intercontraction intervals and voided volume was observed in PNL rats compared with sham rats, but it was not seen in PNL rats with capsaicin pretreatment that desensitizes C-fiber-afferent pathways. LPPs in PNL rats were significantly decreased compared with sham rats. The contractile responses of detrusor muscle strips to phenylephrine, but not to carbachol, were significantly increased in PNL rats. The levels of NGF protein and mRNA in the bladder of PNL rats were significantly increased compared with sham rats. These results suggest that pudendal nerve neuropathy induced by PNL may be one of the potential risk factors for OAB, as well as SUI. Somato-visceral cross sensitization between somatic (pudendal) and visceral (bladder) sensory pathways that increases NGF expression and alpha(1)-adrenoceptor-mediated contractility in the bladder may be involved in this pathophysiological mechanism.     

The role of geriatricians and family practitioners in the treatment of overactive bladder and incontinence

Although the prevalence of overactive bladder (OAB) and that of its symptoms (urinary urge incontinence, urgency, and frequency) increase with age, these conditions are not necessarily normal consequences of aging. Patients who present with urinary symptoms should be evaluated and treated, whether they are living on their own or in a residential, assisted-care, or long-term-care environment. Effective treatment for OAB and urinary incontinence (UI) is available and improves quality of life for the elderly. The primary care physician and geriatrician can accomplish a basic evaluation for UI using a systematic approach, as detailed in the following pages.     

膀胱过度活动症的抗胆碱治疗及其不良反应

膀胱过度活动症(overactive bladder,OAB)是一种令人烦恼的疾病,它影响着人们生活的质量。病人常常表现为尿急,伴有或不伴有急迫性尿失禁,通常有尿频和夜尿的症状。虽然膀胱过度活动症的病因不是很明确,但是抗胆碱药物作为其治疗的基石,在减少膀胱储尿期的收缩,增加膀胱的容量,起着重要的作用。这类药物具有一定的安全性,副作用小,并且有着相似的疗效。尽管如此,当治疗膀胱过度活动时,抗胆碱药物种类的选择,其治疗的预期利弊平衡也应在考虑之中,尤其是合并有中枢神经系统或者心脑血管系统疾病的老年患者。本文通过查阅国内外新近相关的文献,从受体的选择,临床应用和不良反应等方面对7种抗胆碱药物进行综述。     

A Comparative Study on the Efficacy of Solifenacin Succinate in Patients with Urinary Frequency with or without Urgency

Objectives

Patients with overactive bladder (OAB) often have trouble perceiving urgency because of difficulties in distinguishing between urgency and desire to void. Empirical antimuscarinic treatment of patients with frequency only may be reasonable if conservative management has failed. We compared the efficacy of solifenacin in patients with frequency with or without urgency.

Materials and Methods

This multicenter, 12-week, open-label, comparative, non-inferiority clinical trial assessed whether the solifenacin efficacy for frequency without urgency is non-inferior to its efficacy for frequency with urgency. All patients had micturition frequency ≥8 voids/day with or without urgency. Primary efficacy variable: daily frequency change at 12 weeks relative to baseline. Secondary efficacy variables: change at 12 weeks relative to baseline in Patients'' Perception of Bladder Condition (PPBC), OAB Symptom Score (OABSS), and Benefit, Satisfaction, Willingness to continue (BSW) questionnaire.

Results

Of the 286 enrolled patients, 240 (83.9%) completed the study (without urgency n = 115; with urgency n = 125). Full dataset analysis revealed that the groups without and with urgency exhibited significant reductions in daily micturition frequency of −2.49±0.35 (mean ± standard error) and −2.63±0.37, respectively. The lower limit of the 95% two-sided CI of the comparison of the two group means was −1.14, which is smaller than the −0.8 margin of clinical equivalence. The two groups did not differ in improvement in PPBC, OABSS, or BSW scores. Both tolerated the treatment well.

Conclusions

It was not possible to verify that the solifenacin efficacy for frequency alone was non-inferior to its efficacy for OAB. Nevertheless, solifenacin tended to be effective for frequency regardless of urgency.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00979472","term_id":"NCT00979472"}}NCT00979472     

Pathophysiology of overactive bladder and urge urinary incontinence

Storage symptoms such as urgency, frequency, and nocturia, with or without urge incontinence, are characterized as overactive bladder (OAB). OAB can lead to urge incontinence. Disturbances in nerves, smooth muscle, and urothelium can cause this condition. In some respects the division between peripheral and central causes of OAB is artificial, but it remains a useful paradigm for appreciating the interactions between different tissues. Models have been developed to mimic the OAB associated with bladder instability, lower urinary tract obstruction, neuropathic disorders, diabetes, and interstitial cystitis. These models share the common features of increased connectivity and excitability of both detrusor smooth muscle and nerves. Increased excitability and connectivity of nerves involved in micturition rely on growth factors that orchestrate neural plasticity. Neurotransmitters, prostaglandins, and growth factors, such as nerve growth factor, provide mechanisms for bidirectional communication between muscle or urothelium and nerve, leading to OAB with or without urge incontinence.     

Will the Evolution of Overactive Bladder Delivery Systems Increase Patient Compliance?

The negative impact of overactive bladder (OAB) on daily quality of life drives the large market of pharmacotherapy targeted at symptoms of urinary frequency and urgency, with or without urinary urge incontinence. Currently, the primary pharmacologic treatment modality is aimed at modulation of the efferent muscarinic receptors (M2 and M3) predominant in detrusor smooth muscle and responsible for involuntary or unwanted bladder contractions. However, due to drug effects in the muscarinic receptors of the salivary glands and intestinal smooth muscle, as well as extensive first-pass metabolism in the liver and intestinal tract yielding parent drug metabolites, adverse side effects are common and can be quite bothersome. These issues, encountered with many of the oral antimuscarinic formulations, limit their tolerability and affect long-term patient compliance and satisfaction. Thus, the benefit of pharmacotherapy for OAB must be a balance between efficacy and tolerability, also known as therapeutic index. This article reviews the current pharmacologic delivery systems available for the treatment of OAB, patient compliance, and reasons for discontinuation of medication.Key words: Overactive bladder, Pharmacotherapy, Compliance, Antimuscarinic agent, Transdermal delivery systemOveractive bladder syndrome (OAB) is a condition affecting millions of adults in the aging US population, with prevalence rates estimated at 17% in both men and women.¹ Quality of life and symptom bother have become important parameters in the treatment of many disease states, with efficacy of treatment measured by perceived improvements in these variables. OAB is largely characterized by its negative impact on daily quality of life. Specifically, the subjective impact of urinary frequency and urgency (with or without urge incontinence) on psychosocial and physical factors has become an important aspect of caring for this group of patients. The severity and degree of bother associated with OAB symptoms can directly influence a person’s mobility, degree of social isolation, and impairment in work-related productivity, and may also cause clinical depression, disruptions in sleep, and impairment in domestic and sexual life.² In addition, the patient may develop extreme coping strategies including severe, self-imposed fluid restrictions, avoidance of social events and travel, and dependence on costly protective undergarments. Although all of these factors drive patients to seek evaluation and treatment, persistence and compliance with medical OAB therapy remain astoundingly low both in the clinical setting and in large-scale clinical trials. High rates of discontinuation are multifactorial: adverse side effects, lack of perceived efficacy, polypharmacy, medication cost, poor counseling regarding compliance and successful treatment, and dosing frequency. Because adverse side effects are experienced by a significant portion of patients treated with oral antimuscarinic therapy, thereby limiting their long-term utilization, the development of new drug delivery systems for OAB pharmacotherapy has been critical. The focus has been on less frequent dosing intervals with longer acting formulations, reduction in side-effect profile by altering pharmacokinetics of both parent compound and active metabolites, and alternative methods of drug delivery that avoid first-pass liver metabolism.     

Differential perturbation of the interstitial cystitis-associated genes of bladder and urethra in rat model

Interstitial cystitis (IC) is a chronic bladder dysfunction characterized as urinary frequency, urgency, nocturia, and pelvic pain. The changes in urethra may wind up with the bladder changes in structure and functions, however, the functions of the urethra in IC remains elusive. The aim of this study was to understand the perturbed gene expression in urethra, compared with urinary bladder, associated with the defected urodynamics. Using female IC mimic rats, a comprehensive RNA-sequencing combined with a bioinformatics analysis was performed and revealed that IC-specific genes in bladder or urethra. Gene ontology analysis suggested that the cell adhesion or extracellular matrix regulation, intracellular signaling cascade, cardiac muscle tissue development, and second messenger-mediated signaling might be the most enriched cellular processes in IC context. Further study of the effects of these bladder- or urethra-specific genes may suggest underlying mechanism of lower urinary tract function and novel therapeutic strategies against IC.     

Presence of Cleaved Synaptosomal-Associated Protein-25 and Decrease of Purinergic Receptors P2X3 in the Bladder Urothelium Influence Efficacy of Botulinum Toxin Treatment for Overactive Bladder Syndrome

Objectives

To evaluate whether botulinum toxin A (BoNT-A) injection and Lipotoxin (liposomes with 200 U of BoNT-A) instillation target different proteins, including P2X3, synaptic vesicle glycoprotein 2A, and SNAP-25, in the bladder mucosa, leading to different treatment outcomes.

Materials and Methods

This was a retrospective study performed in a tertiary teaching hospital. We evaluated the clinical results of 27 OAB patients treated with intravesical BoNT-A injection (n = 16) or Lipotoxin instillation (n = 11). Seven controls were treated with saline. Patients were injected with 100 U of BoNT-A or Lipotoxinin a single intravesical instillation. The patients enrolled in this study all had bladder biopsies performed at baseline and one month after BoNT-A therapy. Treatment outcome was measured by the decreases in urgency and frequency episodes at 1 month. The functional protein expressions in the urothelium were measured at baseline and after 1 month. The Wilcoxon signed-rank test and ordinal logistic regression were used to compare the treatment outcomes.

Results

Both BoNT-A injection and Lipotoxin instillation treatments effectively decreased the frequency of urgency episodes in OAB patients. Lipotoxin instillation did not increase post-void residual volume. BoNT-A injection effectively cleaved SNAP-25 (p < 0.01). Liposome encapsulated BoNT-A decreased urothelial P2X3 expression in the five responders (p = 0.04), while SNAP-25 was not significantly cleaved.

Conclusions

The results of this study provide a possible mechanism for the therapeutic effects of BoNT-A for the treatment of OAB via different treatment forms. BoNT-A and Lipotoxin treatments effectively decreased the frequency of urgency episodes in patients with OAB.     

Efficacy and Safety of Intravesical OnabotulinumtoxinA Injection on Elderly Patients with Chronic Central Nervous System Lesions and Overactive Bladder

Purpose

Intravesical injection of onabotulinumtoxinA is an effective treatment for overactive bladder (OAB). Nonetheless, the treatment outcome is unclear in OAB patients with central nervous system (CNS) lesions. This study evaluated the efficacy and safety of intravesical onabotulinumtoxinA treatment in elderly patients with chronic cerebrovascular accidents (CVAs), Parkinson’s disease (PD) and dementia.

Materials and Methods

Patients with CVA, PD, dementia, and OAB refractory to antimuscarinic therapy were consecutively enrolled in the study group. Age-matched OAB patients without CNS lesions were selected to serve as a control group. OnabotulinumtoxinA (100 U) was injected into the bladder suburothelium at 20 sites. The clinical effects, adverse events, and urodynamic parameters were assessed at baseline and 3 months post-treatment. The Kaplan-Meier method was used to compare long-term success rates between groups.

Results

A total of 40 patients with OAB due to CVA (23), PD (9), dementia (8) and 160 control patients were included in this retrospetive analysis. Improvement of urgency severity scale, increased bladder capacity and increased post-void residual volume were comparable between the groups at 3 months. Patients with CNS lesions did not experience increased risks of acute urinary retention and urinary tract infection; nonetheless, patients with CVA experienced a higher rate of straining to void. Long-term success rates did not differ between the patients with and without CNS lesions.

Conclusion

Intravesical injection of 100 U of onabotulinumtoxinA effectively decreased urgency symptoms in elderly OAB patients with CNS lesions. The adverse events were acceptable, and long-term effects were comparable to OAB patients in general. Nonetheless, the possibility of longstanding urinary retention and chronic catheterization need careful evaluation for this very vulnerable population before choosing intravesical onabotulinumtoxinA treatment.     

Molecular pathogenesis of interstitial cystitis/bladder pain syndrome based on gene expression

Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic bladder inflammation that leads to chronic bladder pain and urinary urgency and frequency. The presentation of IC/PBS is heterogeneous, and it is classified as ulcerative IC/PBS and nonulcerative IC/PBS. The main cause of IC/PBS is thought to be a persistent inflammatory condition in the bladder, though the actual pathophysiology has not been identified yet. Although the underlying pathophysiology of IC/PBS is not completely understood, several theories for the etiology of this syndrome have been suggested, including deficiency of the glycosaminoglycan covering urothelium surface that results in leaky urothelium infection, immunological etiology, activated mast cells, neural changes, and inflammation. In addition, there are no gold standards for the detection of this disorder to date. So, determination of gene expression and its role in different signaling pathways in the pathogenesis of this heterogeneous disorder contribute to the more efficient cognition of the pathophysiology of this disease and to the design of effective treatments and molecular diagnostic methods for IC/PBS.     

Hyperosmolarity alters micturition: a comparison of urinary bladder motor activity in hyperosmolar and cyclophosphamide-induced models of overactive bladder

Hyperosmolar factors induce the neurogenic inflammatory response, leading to bladder overactivity (OAB). The aim of the study was to compare the bladder motor activity in a hyperosmolar and acute cyclophosphamide (CYP)-induced model of OAB. Furthermore, we set our sights on defining the most physiological model of OAB in experimental practice. Forty-two female rats were divided randomly into 5 groups. All animals underwent cystometry with the usage of isotonic saline or saline of increasing concentration. Acute chemical cystitis was induced by CYP to elicit OAB. The following cystometric parameters were analyzed: basal pressure, threshold pressure, micturition voiding pressure, intercontraction interval, compliance, functional bladder capacity, motility index, and detrusor overactivity index. CYP and hypertonic saline solutions induced OAB. Having been compared with CYP OAB, none of the rats infused with hypertonic solution exhibited macroscopic signs of bladder inflammation. The comparison of CYP and hyperosmolar models of OAB revealed that the greatest similarity existed between the 2080 mOsm/L OAB model and the acute CYP-induced model. We postulate that the 2080 mOsm/L model of OAB can be established as being a less invasive and more physiological model when compared with the CYP-induced OAB model. Additionally, it may also be a more reliable experimental tool for evaluating novel therapeutics for OAB as compared with CYP-induced models.     

New therapeutic approach with extracellular vesicles from stem cells for interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disorder characterized by suprapubic pain and urinary symptoms such as urgency, nocturia, and frequency. The prevalence of IC/BPS is increasing as diagnostic criteria become more comprehensive. Conventional pharmacotherapy against IC/BPS has shown suboptimal effects, and consequently, patients with end-stage IC/BPS are subjected to surgery. The novel treatment strategies should have two main functions, anti-inflammatory action and the regeneration of glycosaminoglycan and urothelium layers. Stem cell therapy has been shown to have dual functions. Mesenchymal stem cells (MSCs) are a promising therapeutic option for IC/BPS, but they come with several shortcomings, such as immune activation and tumorigenicity. MSC-derived extracellular vesicles (MSC-EVs) hold numerous therapeutic cargos and are thus a viable cell-free therapeutic option. In this review, we provide a brief overview of IC/BPS pathophysiology and limitations of the MSC-based therapies. Then we provide a detailed explanation and discussion of therapeutic applications of EVs in IC/BPS as well as the possible mechanisms. We believe our review will give an insight into the strengths and drawbacks of EV-mediated IC/BPS therapy and will provide a basis for further development.     

Efficacy of cinnamon patch treatment for alleviating symptoms of overactive bladder: A double-blind,randomized, placebo-controlled trial

BackgroundCurrent treatments for overactive bladder (OAB) have limited efficacy, low persistence and a high rate of adverse events commonly leading to treatment cessation in clinical practice. Clinicians in Asia commonly use traditional Chinese medicine as an alternative for OAB treatment despite it having uncertain efficacy and safety. To evaluate the efficacy and safety of cinnamon patch (CP) treatment for alleviating symptoms of OAB, a double-blind randomized, placebo-controlled trial was conducted in the present study.Materials and MethodsIn this 6-week randomized clinical trial conducted in an outpatient setting, 66 subjects diagnosed as having OAB were enrolled and treated with a placebo (n=33) or CP (n=33). The OAB symptom score (OABSS) was selected as the primary end point, and a patient perception of bladder condition (PPBC), an urgency severity scale (USS), and post-voiding residual urine (PVR) volume were selected as secondary end points. Statistical analyses were performed with IBM SPSS Statistics 20. Groups were compared using an independent sample t-test, Fisher exact test, and Chi-squared test.ResultsIn total, 66 participants (40 women and 26 men), 60.35 ± 12.77 years of age, were included in the intention-to-treat analyses. Baseline characteristics were comparable between the CP (n ==33) and placebo (n ==33) groups. Treatment with a CP showed statistically significant differences in reductions in OABSS scores (9.70 ± 2.20 to 6.33 ± 2.42), PPBC scores (3.36 ± 0.60 to 2.15 ± 0.83), and USS scores (2.67 ± 0.54 to 1.64 ± 0.60).ConclusionsCompared to a placebo, treatment with CP might be considered an effective and safe complementary therapy for OAB. Further studies employing a positive control, different dosage forms, larger sample sizes, and longer treatment periods are warranted.     

Complementary and alternative therapies as treatment approaches for interstitial cystitis

The management of interstitial cystitis (IC) is predominantly the reduction of the symptoms of frequency, urgency, and pain. Multimodal treatment approaches for IC are helpful in customizing therapy for individual patients. Complementary and alternative therapies are a quintessential addition to the therapeutic armamentarium and frequently include dietary modification, nutraceuticals, bladder training, neuromodulation, stress reduction, and sex therapy. Dietary modification involves elimination of bladder irritants, fluid regulation, and a bowel regimen. Nutraceuticals studied for the treatment of IC include calcium glycerophosphate, L-arginine, mucopolysaccharides, bioflavinoids, and Chinese herbs. Bladder training is effective after pain reduction. The neuromodulation of high-tone pelvic-floor muscle dysfunction is achieved with physical therapy and acupuncture. Stress reduction and sex therapy are best administered by a qualified stress manager and sex therapist. Multimodal, nonconventional management may add efficacy to the treatment of IC.     

Roles of mesenchymal stem cells and exosomes in interstitial cystitis/bladder pain syndrome

Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by several symptoms of higher sensitivity of the lower urinary tract, such as bladder pain/discomfort, urgency, urinary frequency, pelvic pain and nocturia. Although the pathophysiology of IC/BPS is not fully understood, the hypothesis suggests that mast cell activation, glycosaminoglycan (GAG) layer defects, urothelium permeability disruption, inflammation, autoimmune disorder and infection are potential mechanisms. Mesenchymal stem cells (MSCs) have been proven to protect against tissue injury in IC/BPS by migrating into bladders, differentiating into key bladder cells, inhibiting mast cell accumulation and cellular apoptosis, inhibiting inflammation and oxidative stress, alleviating collagen fibre accumulation and enhancing tissue regeneration in bladder tissues. In addition, MSCs can protect against tissue injury in IC/BPS by secreting various soluble factors, including exosomes and other soluble factors, with antiapoptotic, anti‐inflammatory, angiogenic and immunomodulatory properties in a cell‐to‐cell independent manner. In this review, we comprehensively summarized the current potential pathophysiological mechanisms and standard treatments of IC/BPS, and we discussed the potential mechanisms and therapeutic effects of MSCs and MSC‐derived exosomes in alleviating tissue injury in IC/BPS models.     

Cell signaling in interstitial cystitis/painful bladder syndrome

Evidence for several types of cell signaling abnormalities has been presented for patients with interstitial cystitis/painful bladder syndrome (IC/PBS), a poorly understood chronic painful bladder disorder for which currently there is no reliable effective therapy. Increases or decreases in various urine cytokines and growth factors have been found in patient specimens, along with abnormal expression of epithelial differentiation markers, growth factors, cell membrane proteins, neurotransmitters, and other cytokines in tissue biopsies and/or explanted bladder cells from IC/PBS patients. Some of the abnormalities found in bladder epithelial cells from IC/PBS patients have been shown to be induced in normal cells by an antiproliferative factor from IC/PBS bladder epithelial cells that binds to a functional cell membrane receptor (CKAP4/p63). Greater understanding of cell signaling events associated with this debilitating disorder may lead to the development of more effective therapies.     

Inhibition of bladder overactivity by a combination of tibial neuromodulation and tramadol treatment in cats

Our recent study in cats revealed that inhibition of bladder overactivity by tibial nerve stimulation (TNS) depends on the activation of opioid receptors. TNS is a minimally invasive treatment for overactive bladder (OAB), but its efficacy is low. Tramadol (an opioid receptor agonist) is effective in treating OAB but elicits significant adverse effects. This study was to determine if a low dose of tramadol (expected to produce fewer adverse effects) can enhance the TNS inhibition of bladder overactivity. Bladder overactivity was induced in α-chloralose-anesthetized cats by an intravesical infusion of 0.25% acetic acid (AA) during repeated cystometrograms (CMGs). TNS (5 Hz) at two to four times the threshold intensity for inducing toe movement was applied during CMGs before and after tramadol (0.3-7 mg/kg iv) to examine the interaction between the two treatments. AA irritation significantly reduced bladder capacity to 24.8 ± 3.3% of the capacity measured during saline infusion. TNS alone reversibly inhibited bladder overactivity and significantly increased bladder capacity to 50-60% of the saline control capacity. Tramadol administered alone in low doses (0.3-1 mg/kg) did not significantly change bladder capacity, whereas larger doses (3-7 mg/kg) increased bladder capacity (50-60%). TNS in combination with tramadol (3-7 mg/kg) completely reversed the effect of AA. Tramadol also unmasked a prolonged (>2 h) TNS inhibition of bladder overactivity that persisted after termination of the stimulation. The results suggest a novel treatment strategy for OAB by combining tibial neuromodulation with a low dose of tramadol, which is minimally invasive with a potentially high efficacy and fewer adverse effects.     

Urinary Bladder Distention Evoked Visceromotor Responses as a Model for Bladder Pain in Mice

Approximately 3-8 million people in the United States suffer from interstitial cystitis/bladder pain syndrome (IC/BPS), a debilitating condition characterized by increased urgency and frequency of urination, as well as nocturia and general pelvic pain, especially upon bladder filling or voiding. Despite years of research, the cause of IC/BPS remains elusive and treatment strategies are unable to provide complete relief to patients. In order to study nervous system contributions to the condition, many animal models have been developed to mimic the pain and symptoms associated with IC/BPS. One such murine model is urinary bladder distension (UBD). In this model, compressed air of a specific pressure is delivered to the bladder of a lightly anesthetized animal over a set period of time. Throughout the procedure, wires in the superior oblique abdominal muscles record electrical activity from the muscle. This activity is known as the visceromotor response (VMR) and is a reliable and reproducible measure of nociception. Here, we describe the steps necessary to perform this technique in mice including surgical manipulations, physiological recording, and data analysis. With the use of this model, the coordination between primary sensory neurons, spinal cord secondary afferents, and higher central nervous system areas involved in bladder pain can be unraveled. This basic science knowledge can then be clinically translated to treat patients suffering from IC/BPS.