Stress-induced symptom exacerbation: Stress increases voiding frequency, somatic sensitivity, and urinary bladder inflammation when combined with low concentration cyclophosphamide treatment in mice

Abstract

Symptom exacerbation due to stress is prevalent in many disease states, including functional disorders of the urinary bladder (e.g., overactive bladder (OAB), interstitial cystitis/bladder pain syndrome (IC/BPS)); however, the mechanisms underlying the effects of stress on micturition reflex function are unclear. In this study we designed and evaluated a stress-induced symptom exacerbation (SISE) mouse model that demonstrates increased urinary frequency and somatic (pelvic and hindpaw) sensitivity. Cyclophosphamide (CYP) (35 mg/kg; i.p., every 48 hours for a total of 4 doses) or 7 days of repeated variate stress (RVS) did not alter urinary bladder function or somatic sensitivity; however, both CYP alone and RVS alone significantly (p ≤ 0.01) decreased weight gain and increased serum corticosterone. CYP treatment when combined with RVS for 7 days (CYP+RVS) significantly (p ≤ 0.01) increased serum corticosterone, urinary frequency and somatic sensitivity and decreased weight gain. CYP+RVS exposure in mice significantly (p ≤ 0.01) increased (2.6-fold) voiding frequency as we determined using conscious, open-outlet cystometry. CYP+RVS significantly (p ≤ 0.05) increased baseline, threshold, and peak micturition pressures. We also evaluated the expression of NGF, BDNF, CXC chemokines and IL-6 in urinary bladder in CYP alone, RVS alone and CYP+RVS mouse cohorts. Although all treatments or exposures increased urinary bladder NGF, BDNF, CXC and IL-6 content, CYP+RVS produced the largest increase in all inflammatory mediators examined. These results demonstrated that CYP alone or RVS alone creates a change in the inflammatory environment of the urinary bladder but does not result in a change in bladder function or somatic sensitivity until CYP is combined with RVS (CYP+RVS). The SISE model of CYP+RVS will be useful to develop testable hypotheses addressing underlying mechanisms where psychological stress exacerbates symptoms in functional bladder disorders leading to identification of targets and potential treatments.

Intravesical Botulinum Toxin Injection Plus Hydrodistention Is More Effective in Patients with Bladder Pain-Predominant Interstitial Cystitis/Bladder Pain Syndrome

“…In addition, this study also noted more ANS comorbidities in all patients with NHIC, signifying that NHIC is not a single disorder but rather encompasses a spectrum of distinct disorders [ 36 ]. Chronic inflammation and oxidative stress damage the bladder urothelium [ 37 ], and stress increases the voiding frequency, somatic sensitivity, urinary bladder nerve growth factor, and BDNF expression [ 38 ]. Based on these therapeutic mechanisms, reducing inflammation, pain control, protecting epithelial denudation, and stabilizing psychological status are the treatment goals.…”

Temporally complex inflammatory networks in an animal model reveal signatures for interstitial cystitis and bladder pain syndrome phenotype

“…While CYP induced cystitis is not a direct and perfect model of IC/ BPS, it is one of the widely used animal models to study IC/BPS pathophysiology. 29 CYP has been used to study inflammation in the skin as well. In contrast to the skin, bladder mucosa is highly vulnerable to free radicals generated by CYP and therefore, the expression of same inflammatory mediators as expressed locally in skin in response to CYP (IL-1, IL6, IL-18, GRO-a, MCP-1, and TNF-a) are higher because the high metabolic rate of bladder mucosa can sustain the high protein expression rate that cannot be matched by inflammatory foci on skin.…”

“…33 Indeed, bladder centric BPS/IC is associated with vascular injury and vasculitis with bloated endothelial cells, focal degeneration and fragmentation. [34][35][36] Additionally, future studies should seek to model how these inflammatory networks are perturbed by current medical and physiologic treatment for IC/BPS 29 We foresee that computational models of IC/BPS can serve as a digital space for integrating the wide range of data relevant data for IC/BPS pathology, improving diagnosis, and reducing the delay in treatment. This work suggests that the inflammatory characteristics of IC/BPS are not static but dynamic and temporally evolve and resolve with time.…”

Latest insights into the pathophysiology of bladder pain syndrome/interstitial cystitis

“…However, it seems that not only inflammation has an effect on expression of chemokines including NGF but also psychological stress as demonstrated by Girard et al [42 ▪▪ ]. In a mice model, they were able to demonstrate that CYP and repeated variable stress led to significantly higher expression of inflammatory mediators than CYP alone [42 ▪▪ ]. This observation could explain why psychological stress in humans with BPS/IC can lead to symptom exacerbation.…”

“…The same group published an article showing that pharmacological inhibition of the mentioned receptors was associated with significant improvement of LUT symptoms in the acute and chronic cystitis conditions [41 ▪ ]. However, it seems that not only inflammation has an effect on expression of chemokines including NGF but also psychological stress as demonstrated by Girard et al [42 ▪▪ ]. In a mice model, they were able to demonstrate that CYP and repeated variable stress led to significantly higher expression of inflammatory mediators than CYP alone [42 ▪▪ ].…”