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      Animal Modelling of Interstitial Cystitis/Bladder Pain Syndrome

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          Abstract

          The etiology of interstitial cystitis/bladder pain syndrome (IC/BPS) remains elusive and may involve multiple causes. To better understand its pathophysiology, many efforts have been made to create IC/BPS models. Most existing models of IC/BPS strive to recreate bladder-related features by applying noxious intravesical or systemic stimuli to healthy animals. These models are useful to help understand various mechanisms; however, they are limited to demonstrating how the bladder and nervous system respond to noxious stimuli, and are not representative of the complex interactions and pathophysiology of IC/BPS. To study the various factors that may be relevant for IC/BPS, at least 3 different types of animal models are commonly used: (1) bladder-centric models, (2) models with complex mechanisms, and (3) psychological and physical stressors/natural disease models. It is obvious that all aspects of the human disease cannot be mimicked by a single model. It may be the case that several models, each contributing to a piece of the puzzle, are required to recreate a reasonable picture of the pathophysiology and time course of the disease(s) diagnosed as IC/BPS, and thus to identify reasonable targets for treatment.

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          Most cited references51

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          Increased excitability of afferent neurons innervating rat urinary bladder after chronic bladder inflammation.

          The properties of bladder afferent neurons in L6 and S1 dorsal root ganglia of adult rats were evaluated after chronic bladder inflammation induced by 2 week treatment with cyclophosphamide (CYP; 75 mg/kg). Whole-cell patch-clamp recordings revealed that most (70%) of the dissociated bladder afferent neurons from control rats were capsaicin sensitive, with high-threshold long-duration action potentials that were not blocked by tetrodotoxin (TTX; 1 microM). These neurons exhibited membrane potential relaxations during voltage responses elicited by depolarizing current pulses and phasic firing during sustained membrane depolarization. After CYP treatment, a similar proportion (71%) of bladder afferent neurons were capsaicin sensitive with TTX-resistant spikes. However, the neurons were significantly larger in size (diameter 29.6 +/- 1.0 micrometer vs 23.6 +/- 0.8 micrometer in controls). TTX-resistant bladder afferent neurons from CYP-treated rats exhibited lower thresholds for spike activation (-25.4 +/- 0.5 mV) than those from control rats (-21.4 +/- 0.9 mV) and did not exhibit membrane potential relaxation during depolarization. Seventy percent of TTX-resistant bladder afferent neurons from CYP-treated rats exhibited tonic firing (average 12.3 +/- 1.4 spikes during a 500 msec depolarizing pulse) versus phasic firing (1.2 +/- 0.2 spikes) in normal bladder afferent neurons. Application of 4-aminopyridine (1 mM) to normal TTX-resistant bladder afferent neurons mimicked the changes in firing properties after CYP treatment. The peak density of an A-type K+ current (IA) during depolarizations to 0 mV in TTX-resistant bladder afferent neurons from CYP-treated rats was significantly smaller (42.9 pA/pF) than that from control rats (109.4 pA/pF), and the inactivation curve of the IA current was displaced to more hyperpolarized levels by approximately 15 mV after CYP treatment. These data suggest that chronic inflammation induces somal hypertrophy and increases the excitability of C-fiber bladder afferent neurons by suppressing IA channels. Similar electrical changes in sensory pathways may contribute to cystitis-induced pain and hyperactivity of the bladder.
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            Biopsy features are associated with primary symptoms in interstitial cystitis: results from the interstitial cystitis database study.

            The purpose of this study was to investigate associations between bladder biopsy features and urinary symptoms for patients enrolled in the Interstitial Cystitis Database (ICDB) Study. Bladder biopsies were obtained during baseline screening in the ICDB Study and were evaluated for histopathologic features. Multivariable models for nighttime voiding frequency, urinary urgency, and pain were developed, incorporating biopsy features from the most diseased area of the bladder as predictors, adjusting for significant clinical factors, and clinical center variation. Among 204 interstitial cystitis (IC) patients providing biopsy specimens, cystoscopic pathology findings were not statistically associated (P >0.1) with primary IC symptoms, although the presence of Hunner's ulcer (n = 12) was suggestive of increased urinary frequency. Within a multivariable predictive model for nighttime voiding frequency, adjusting for age and minimum volume per void, 4 pathology features were noted: (1) mast cell count in lamina propria on tryptase stain; (2) complete loss of urothelium; (3) granulation tissue in lamina propria; and (4) vascular density in lamina propria on factor VIII (F8) stain were statistically significant (P <0.01). Similarly, in a multivariable model for urinary urgency, minimum volume, and percentage of submucosal granulation tissue remained statistically significant (P <0.01). Finally, the percentage of mucosa denuded of urothelium and the percentage of submucosal hemorrhage remained highly associated (P <0.01) with pain in a multivariable predictive model. The fact that the presence or severity of glomerulations was not selected for any of these predictive models suggests that cystoscopic findings of glomerulations are not predictive of IC symptoms. Furthermore, these results suggest an important role for certain pathologic features in the predictive modeling of IC symptoms.
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              Functional characterization of a chronic cyclophosphamide-induced overactive bladder model in mice.

              To describe a new mouse model of overactive bladder (OAB) at the histological level, pain, voiding behavior, and urodynamics, while assessing the physiological state of mice. This paper compares the pathophysiological features of mice that received intraperitoneal injections of cyclophosphamide (CYP) (40 and 80  mg/kg - body weight) every 2 days for 7 days. Specifically, the heart rate, the body temperature, and the general activity were assessed by telemetry. The abdominal sensitivity was determined with Von Frey filaments. Voiding behavior and detrusor activity were respectively quantified by urine spotting experiments and cystometry. Hematoxylin & Eosin staining was performed to detect inflammation in tissue and NGF concentration in urine was quantified. Affected mice exhibit clearly an OAB characterized by an increase in the number of voiding events and an urodynamically-demonstrated detrusor overactivity associated with referred hyperalgesia. The injected mice displayed inflamed bladder, urothelial hyperplasia, and increased NGF concentration in urine in dose dependant manner. However, the physiological features of mice with CYP-induced cystitis are not changed. We can show that this model of chronic OAB with pain in mice fits more closely to the clinical signs of patients with OAB than the available animal models (acute and chronic) and will therefore be useful to highlight potential drug targets in genetically modified mice in the future. Copyright © 2011 Wiley Periodicals, Inc.
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                Author and article information

                Journal
                Int Neurourol J
                Int Neurourol J
                INJ
                International Neurourology Journal
                Korean Continence Society
                2093-4777
                2093-6931
                January 2018
                31 January 2018
                : 22
                : Suppl 1
                : S3-9
                Affiliations
                [1 ]Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
                [2 ]Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
                [3 ]Institute for Regenerative Medicine, Wake Forest University School of Medicine, Winston Salem, NC, USA
                [4 ]Institute of Laboratory Medicine, Lund University, Lund, Sweden
                Author notes
                Corresponding author: Lori Birder http://orcid.org/0000-0002-3393-2256 University of Pittsburgh School of Medicine, A 1217 Scaife Hall, 3550 Terrace Street, Pittsburgh, PA 15261, USA E-mail: lbirder@ 123456pitt.edu / Tel: +1-412-383-7368 / Fax: +1-412-648-7197
                Author information
                http://orcid.org/0000-0002-3393-2256
                http://orcid.org/0000-0003-0665-3486
                Article
                inj-1835062-531
                10.5213/inj.1835062.531
                5798638
                29385788
                3dd3dd4e-acf9-4af8-8cdc-e47066b68c9d
                Copyright © 2018 Korean Continence Society

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 18 November 2017
                : 3 January 2018
                Categories
                Review Article

                Neurology
                interstitial cystitis,bladder pain syndrome,animal models,inflammation,mucosa,stress
                Neurology
                interstitial cystitis, bladder pain syndrome, animal models, inflammation, mucosa, stress

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