How does the lower urinary tract contribute to bladder sensation? ICI-RS 2023.

AIM: Bladder sensation is critical for coordinating voluntary micturition to maintain healthy bladder function. Sensations are initiated by the activation of sensory afferents that innervate throughout the bladder wall. However, the physiological complexity that underlies the initiation of bladder sensory signaling in health and disease remains poorly understood. This review summarises the latest knowledge of the mechanisms underlying the generation of bladder sensation and identifies key areas for future research. METHODS: Experts in bladder sensory signaling reviewed the literature on how the lower urinary tract contributes to bladder sensation and identified key research areas for discussion at the 10th International Consultation on Incontinence-Research Society. RESULTS: The importance of bladder sensory signals in maintaining healthy bladder function is well established. However, better therapeutic management of bladder disorders with exaggerated bladder sensation, including overactive bladder syndrome (OAB) and interstitial cystitis/bladder pain syndrome (IC/BPS) is limited by a lack of knowledge in a number of key research areas including; the contribution of different nerves (pudendal, pelvic, hypogastric) to filling sensations in health and disease; the relative contribution of stretch sensitive (muscular) and stretch-insensitive (mucosal) afferents to bladder sensation in health and disease; the direct and indirect contributions of the muscularis mucosae to bladder contraction and sensation; and the impact of manipulating urothelial release factors on bladder sensation. CONCLUSION: Disturbances in bladder sensory signaling can have severe consequences for bladder sensation and function including the development of OAB and IC/BPS. Advancing therapeutic treatments for OAB and IC/BPS requires a deeper understanding of the mechanisms underlying the generation of bladder sensation, and key areas for future research have been identified.

Beyond the urothelium: Interplay between autonomic nervous system and bladder inflammation in urinary tract infection, bladder pain syndrome with interstitial cystitis and neurogenic lower urinary tract dysfunction in spinal cord injury-ICI-RS 2023.

INTRODUCTION: Inflammation and neuronal hypersensitivity are reactive protective mechanisms after urothelial injury. In lower urinary tract dysfunctions (LUTD), such as urinary tract infection (UTI), bladder pain syndrome with interstitial cystitis (BPS/IC) and neurogenic LUTD after spinal cord injury (SCI), chronic inflammation can develop. It is unclear how the protective reactionary inflammation escalates into chronic disease in some patients. METHODS: During its 2023 meeting in Bristol, the International Consultation on Incontinence-Research Society (ICI-RS) reviewed the urothelial and inflammatory changes after UTI, BPS/IC and SCI. Potential factors contributing to the evolution into chronic disease were explored in a think-tank. RESULTS: Five topics were discussed. (1) Visceral fat metabolism participates in the systemic pro-inflammatory effect of noradrenalin in BPS/IC and SCI. Sympathetic nervous system-adipocyte-bladder crosstalk needs further investigation. (2) Sympathetic hyperactivity also potentiates immune depression in SCI and needs to be investigated in BPS/IC. Gabapentin and tumor necrosis factor-α are promising research targets. (3) The exact peripheral neurons involved in the integrative protective unit formed by nervous and immune systems need to be further identified. (4) Neurotransmitter changes in SCI and BPS/IC: Neurotransmitter crosstalk needs to be considered in identifying new therapeutic targets. (5) The change from eubiosis to dysbiosis in SCI can contribute to UTI susceptibility and needs to be unraveled. CONCLUSIONS: The think-tank discussed whether visceral fat metabolism, immune depression through sympathetic hyperactivity, peripheral nerves and neurotransmitter crosstalk, and the change in microbiome could provide explanations in the heterogenic development of chronic inflammation in LUTD. High-priority research questions were identified.

Animal models of interstitial cystitis/bladder pain syndrome.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic disorder characterized by pelvic and/or bladder pain, along with lower urinary tract symptoms that have a significant impact on an individual's quality of life. The diverse range of symptoms and underlying causes in IC/BPS patients pose a significant challenge for effective disease management and the development of new and effective treatments. To facilitate the development of innovative therapies for IC/BPS, numerous preclinical animal models have been developed, each focusing on distinct pathophysiological components such as localized urothelial permeability or inflammation, psychological stress, autoimmunity, and central sensitization. However, since the precise etiopathophysiology of IC/BPS remains undefined, these animal models have primarily aimed to replicate the key clinical symptoms of bladder hypersensitivity and pain to enhance the translatability of potential therapeutics. Several animal models have now been characterized to mimic the major symptoms of IC/BPS, and significant progress has been made in refining these models to induce chronic symptomatology that more closely resembles the IC/BPS phenotype. Nevertheless, it's important to note that no single model can fully replicate all aspects of the human disease. When selecting an appropriate model for preclinical therapeutic evaluation, consideration must be given to the specific pathology believed to underlie the development of IC/BPS symptoms in a particular patient group, as well as the type and severity of the model, its duration, and the proposed intervention's mechanism of action. Therefore, it is likely that different models will continue to be necessary for preclinical drug development, depending on the unique etiology of IC/BPS being investigated.

The T-type calcium channel Ca V 3.2 regulates bladder afferent responses to mechanical stimuli.

ABSTRACT: The bladder wall is innervated by a complex network of afferent nerves that detect bladder stretch during filling. Sensory signals, generated in response to distension, are relayed to the spinal cord and brain to evoke physiological and painful sensations and regulate urine storage and voiding. Hyperexcitability of these sensory pathways is a key component in the development of chronic bladder hypersensitivity disorders including interstitial cystitis/bladder pain syndrome and overactive bladder syndrome. Despite this, the full array of ion channels that regulate bladder afferent responses to mechanical stimuli have yet to be determined. Here, we investigated the role of low-voltage-activated T-type calcium (Ca V 3) channels in regulating bladder afferent responses to distension. Using single-cell reverse-transcription polymerase chain reaction and immunofluorescence, we revealed ubiquitous expression of Ca V 3.2, but not Ca V 3.1 or Ca V 3.3, in individual bladder-innervating dorsal root ganglia neurons. Pharmacological inhibition of Ca V 3.2 with TTA-A2 and ABT-639, selective blockers of T-type calcium channels, dose-dependently attenuated ex-vivo bladder afferent responses to distension in the absence of changes to muscle compliance. Further evaluation revealed that Ca V 3.2 blockers significantly inhibited both low- and high-threshold afferents, decreasing peak responses to distension, and delayed activation thresholds, thereby attenuating bladder afferent responses to both physiological and noxious distension. Nocifensive visceromotor responses to noxious bladder distension in vivo were also significantly reduced by inhibition of Ca V 3 with TTA-A2. Together, these data provide evidence of a major role for Ca V 3.2 in regulating bladder afferent responses to bladder distension and nociceptive signalling to the spinal cord.

BCG induced lower urinary tract symptoms during treatment for NMIBC-Mechanisms and management strategies.

Non-muscle invasive bladder cancer (NMIBC) accounts for ~70-75% of total bladder cancer tumors and requires effective early intervention to avert progression. The cornerstone of high-risk NMIBC treatment involves trans-urethral resection of the tumor followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. However, BCG therapy is commonly accompanied by significant lower urinary tract symptoms (LUTS) including urinary urgency, urinary frequency, dysuria, and pelvic pain which can undermine treatment adherence and clinical outcomes. Despite this burden, the mechanisms underlying the development of BCG-induced LUTS have yet to be characterized. This review provides a unique perspective on the mechanisms thought to be responsible for the development of BCG-induced LUTS by focussing on the sensory nerves responsible for bladder sensory transduction. This review focuses on how the physiological response to BCG, including inflammation, urothelial permeability, and direct interactions between BCG and sensory nerves could drive bladder afferent sensitization leading to the development of LUTS. Additionally, this review provides an up-to-date summary of the latest clinical data exploring interventions to relieve BCG-induced LUTS, including therapeutic targeting of bladder contractions, inflammation, increased bladder permeability, and direct inhibition of bladder sensory signaling. Addressing the clinical burden of BCG-induced LUTS holds significant potential to enhance patient quality of life, treatment compliance, and overall outcomes in NMIBC management. However, the lack of knowledge on the pathophysiological mechanisms that drive BCG-induced LUTS has limited the development of novel and efficacious therapeutic options. Further research is urgently required to unravel the mechanisms that drive BCG-induced LUTS.

Urinary Tract Infection in Overactive Bladder: An Update on Pathophysiological Mechanisms.

Overactive bladder (OAB) is a clinical syndrome defined by urinary urgency, increased daytime urinary frequency and/or nocturia, with or without urinary incontinence, that affects approximately 11% of the western population. OAB is accepted as an idiopathic disorder, and is charactersied clinically in the absence of other organic diseases, including urinary tract infection. Despite this, a growing body of research provides evidence that a significant proportion of OAB patients have active bladder infection. This review discusses the key findings of recent laboratory and clinical studies, providing insight into the relationship between urinary tract infection, bladder inflammation, and the pathophysiology of OAB. We summarise an array of clinical studies that find OAB patients are significantly more likely than control patients to have pathogenic bacteria in their urine and increased bladder inflammation. This review reveals the complex nature of OAB, and highlights key laboratory studies that have begun to unravel how urinary tract infection and bladder inflammation can induce urinary urgency and urinary frequency. The evidence presented in this review supports the concept that urinary tract infection may be an underappreciated contributor to the pathophysiology of some OAB patients.

TGR5 agonists induce peripheral and central hypersensitivity to bladder distension.

The mechanisms underlying chronic bladder conditions such as interstitial cystitis/bladder pain syndrome (IC/BPS) and overactive bladder syndrome (OAB) are incompletely understood. However, targeting specific receptors mediating neuronal sensitivity to specific stimuli is an emerging treatment strategy. Recently, irritant-sensing receptors including the bile acid receptor TGR5, have been identified within the viscera and are thought to play a key role in neuronal hypersensitivity. Here, in mice, we identify mRNA expression of TGR5 (Gpbar1) in all layers of the bladder as well as in the lumbosacral dorsal root ganglia (DRG) and in isolated bladder-innervating DRG neurons. In bladder-innervating DRG neurons Gpbar1 mRNA was 100% co-expressed with Trpv1 and 30% co-expressed with Trpa1. In vitro live-cell calcium imaging of bladder-innervating DRG neurons showed direct activation of a sub-population of bladder-innervating DRG neurons with the synthetic TGR5 agonist CCDC, which was diminished in Trpv1-/- but not Trpa1-/- DRG neurons. CCDC also activated a small percentage of non-neuronal cells. Using an ex vivo mouse bladder afferent recording preparation we show intravesical application of endogenous (5α-pregnan-3ß-ol-20-one sulphate, Pg5α) and synthetic (CCDC) TGR5 agonists enhanced afferent mechanosensitivity to bladder distension. Correspondingly, in vivo intravesical administration of CCDC increased the number of spinal dorsal horn neurons that were activated by bladder distension. The enhanced mechanosensitivity induced by CCDC ex vivo and in vivo was absent using Gpbar1-/- mice. Together, these results indicate a role for the TGR5 receptor in mediating bladder afferent hypersensitivity to distension and thus may be important to the symptoms associated with IC/BPS and OAB.

A syngeneic inoculation mouse model of endometriosis that develops multiple comorbid visceral and cutaneous pain like behaviours.

ABSTRACT: Endometriosis is a chronic and debilitating condition, commonly characterised by chronic pelvic pain (CPP) and infertility. Chronic pelvic pain can be experienced across multiple pelvic organs, with comorbidities commonly effecting the bowel, bladder, and vagina. Despite research efforts into endometriosis pathophysiology, little is known about how endometriosis induces CPP, and as such, therapeutic interventions are lacking. The aim of this study was to characterise a syngeneic mouse model of endometriosis that mimics naturally occurring retrograde menstruation, thought to precede endometriosis development in patients, and determine whether these mice exhibit signs of CPP and altered behaviour. We characterised the development of endometriosis over 10 weeks following uterine tissue inoculation, measured in vivo and ex vivo hypersensitivity to mechanical stimuli across multiple visceral organs, and assessed alterations in animal spontaneous behaviour. We confirmed that inoculated uterine horn tissue formed into endometriosis lesions throughout the peritoneal cavity, with significant growth by 8 to 10 weeks post inoculation. Additionally, we found that mice with fully developed endometriosis displayed hypersensitivity evoked by (1) vaginal distension, (2) colorectal distension, (3) bladder distension, and (4) cutaneous thermal stimulation, compared to their sham counterparts. Moreover, endometriosis mice displayed alterations in spontaneous behaviour indicative of (5) altered bladder function and (6) anxiety. This model creates a foundation for mechanistical studies into the diffuse CPP associated with endometriosis and the development of targeted therapeutic interventions to improve the quality of life of women with endometriosis.

Guanylate cyclase-C agonists as peripherally acting treatments of chronic visceral pain.

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3',5'-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.