Experimentally Induced Bladder Permeability Evokes Bladder Afferent Hypersensitivity in the Absence of Inflammation.

Luke Grundy,Ashlee Caldwell,Beverley Greenwood Van-Meervald,Gerhard Hannig,Amanda Lumsden,Stuart M. Brierley,Ehsan Mohammadi

doi:10.3389/fnins.2020.590871

Abstract

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic urological condition characterised by urinary urgency, frequency and pelvic pain, that significantly impacts the quality of life for ∼5% of women. Bladder sensation is coordinated by primary afferent sensory neurons that innervate the bladder wall, translating bladder stretch into signals that travel to the brain via the spinal cord. Whilst the pathophysiology of IC/BPS remains unknown, an increase in the permeability of the bladder urothelium has been proposed as an initiating cause. Here we experimentally increased bladder permeability and tracked bladder afferent sensitivity for up to 28 days. We found that one day after increasing bladder epithelial permeability with in vivo bladder infusion of protamine sulfate, mechanosensitive bladder afferents exhibited significant hypersensitivity to bladder filling. This mechanical hypersensitivity was characterised by significantly increased peak afferent firing rates and a decrease in the activation threshold of individual afferents. Bladder afferent hypersensitivity occurred in the absence of inflammation and changes in bladder muscle compliance, indicating a direct sensitisation of peripheral afferent endings. Bladder afferent mechanosensitive responses to distension returned to control levels by day 7 post-protamine sulfate treatment and remained at control levels at 28-days post-treatment. Here we demonstrate, contrary to the prevailing hypothesis, that increased bladder permeability alone does not induce chronic bladder afferent sensitisation. Whilst experimentally induced changes in bladder permeability are able to induce transient bladder afferent hypersensitivity in the absence of inflammation, highly regulated homeostatic mechanisms exist to rapidly repair the urothelial barrier and normalise bladder afferent mechanosensitivity. Together, these data suggest that additional pathophysiology is required to induce chronic bladder dysfunction.

Highlights

Interstitial cystitis/bladder pain syndrome (IC/BPS), is a common urological condition characterised by persistent or recurrent chronic pelvic pain that is often accompanied by urinary urgency and/or frequency (Grundy et al, 2018a; Akiyama et al, 2019)
As increases in the permeability or breakdown of the bladder urothelium have commonly been associated with IC/BPS symptoms, and it is known that bladder afferent sensory neurons are located in close proximity to the urothelium (Spencer et al, 2018), we hypothesised that the bladder hyperalgesia occurring with increased urothelial permeability is via a sensitisation of these afferent neurons to bladder distension
We observed a significant increase in bladder afferent mechanosensitivity from bladders 1 day after protamine sulfate treatment, but no change in mechanosensitivity from mice receiving the sham vehicle infusion (Figures 1A-C)

Summary

Introduction

Interstitial cystitis/bladder pain syndrome (IC/BPS), is a common urological condition characterised by persistent or recurrent chronic pelvic pain that is often accompanied by urinary urgency and/or frequency (Grundy et al, 2018a; Akiyama et al, 2019). The bladder wall contains a dense network of afferent nerves found both in the detrusor smooth muscle, and in close proximity to the bladder lumen and urothelium (Kanda et al, 2016; Spencer et al, 2018). These afferents respond directly to stretch, exhibiting firing rates that closely encode intravesical pressure, and regulate the autonomic circuits responsible for bladder storage (Fowler et al, 2008; Grundy et al, 2019a,b). Whilst the urothelium has been shown to exhibit sensory functions (Birder and Andersson, 2013), the primary role of the urothelium is to provide a blood/urine barrier between the potentially toxic levels of urea, ammonia, and other noxious metabolites found within the urine and the underlying interstitium of the bladder (Lasicet al., 2015)

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