Animal Models of Urologic Chronic Pelvic Pain Syndromes: Findings From the Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network

Abstract

Objectives To describe the approach taken by MAPP (Multi-Disciplinary Approach to the Study of Chronic Pelvic Pain) Research Network investigators to advance the utility of UCPPS (urologic chronic pelvic pain syndromes) animal models. Methods A multidisciplinary team of investigators representing basic science and clinical expertise defined key phenotypic criteria for rodent models of UCPPS. UCPPS symptoms were prioritized based on their clinical significance. Methods for quantifying animal correlates to patient symptoms were developed. The methods were implemented across proposed rodent models for evaluation and comparison of animals for phenotypic characteristics relevant to human symptomatology. Results Pelvic pain and urinary frequency were deemed primary features of human UCPPS and were prioritized for assessment in animals. Nociception was quantified using visceromotor response to bladder distention, and by applying von Frey filaments to the lower abdomen (referred tactile allodynia). Micturition activity was assessed as free voiding using micturition cages or blotting pad assays, and in response to bladder filling by cystometry. Models varied in both depth of characterization and degree of recapitulating pelvic pain and urinary frequency characteristics of UCPPS. Conclusion Rodent models that reflect multiple, key characteristics of human UCPPS may be identified and provide enhanced clinical significance to mechanistic studies. We have developed a strategy for evaluating current and future animal models of UCPPS based on human symptomatology. This approach provides a foundation for improved translation between mechanistic studies in animals and clinical research, and serves as a validation strategy for assessing validity of models for symptom-driven disorders of unknown etiology.

Evidence for the Role of Mast Cells in Cystitis-Associated Lower Urinary Tract Dysfunction: A Multidisciplinary Approach to the Study of Chronic Pelvic Pain Research Network Animal Model Study

“…Baseline voiding habits were recorded for comparison. As observed previously [27], URO-OVA mice developed significant changes in voiding habits after cystitis induction (Table 2). These changes included decreased mean volume voided per micturition ( p = 0.0053), decreased maximum volume voided per micturition ( p = 0.012), and increased total number of voids ( p = 0.0002).…”

“…However, despite these observations, the role of mast cells in cystitis-associated LUTD has not been identified. In this study we used a transgenic EAC model (URO-OVA), which resembles many clinical features of IC/BPS including increased bladder mast cell counts, pelvic pain, and voiding dysfunction [25,27], to investigate whether mast cells play a role in cystitis-associated LUTD.…”

“…Using genetic engineering technology, we previously developed a transgenic EAC model (URO-OVA) that expresses the membrane form of the model antigen ovalbumin (OVA) as a self-antigen on the urothelium and develops bladder inflammation at 7–14 days after adoptive transfer of OVA-specific T cells for cystitis induction [25,26]. The URO-OVA model resembles many clinical features of IC/BPS including increased bladder mast cell counts, pelvic pain, and LUTD [25,27]. Here we used this transgenic EAC model to identify the role of mast cells in cystitis-associated LUTD.…”

Protease activated‐receptor 4 activation as a model of persistent bladder pain: Essential role of macrophage migration inhibitory factor and high mobility group box 1

“…19,20 Micturition changes can be evaluated in awake and/or anesthetized animals. 21 The persistent model described in this experiment showed bladder nociception (as determined by VF testing, as we tested behavior daily) over several days while showing no changes in awake micturition testing (urinary frequency/volume) or bladder histology. These features make this model suitable for studying the mechanisms of bladder pain in the absence of micturition changes caused by bladder injury.…”

“…The pain component of IC/BPS models is most commonly evaluated using VF testing of abdominal mechanical hypersensitivity in awake animals . Micturition changes can be evaluated in awake and/or anesthetized animals . The persistent model described in this experiment showed bladder nociception (as determined by VF testing, as we tested behavior daily) over several days while showing no changes in awake micturition testing (urinary frequency/volume) or bladder histology.…”