Urinary bladder hypersensitivity and dysfunction in female mice following early life and adult stress

Abstract

Early adverse events have been shown to increase the incidence of interstitial cystitis/painful bladder syndrome in adulthood. Despite high clinical relevance and reports of stress-related symptom exacerbation, animal models investigating the contribution of early life stress to female urological pain are lacking. We examined the impact of neonatal maternal separation (NMS) on bladder sensitivity and visceral neuroimmune status both prior-to, and following, water avoidance stress (WAS) in adult female mice. The visceromotor response to urinary bladder distension was increased at baseline and 8d post-WAS in NMS mice, while colorectal sensitivity was transiently increased 1d post-WAS only in naïve mice. Bladder micturition rate and output, but not fecal output, were also significantly increased following WAS in NMS mice. Changes in gene expression involved in regulating the stress response system were observed at baseline and following WAS in NMS mice, and WAS reduced serum corticosterone levels. Cytokine and growth factor mRNA levels in the bladder, and to a lesser extent in the colon, were significantly impacted by NMS and WAS. Peripheral mRNA levels of stress-responsive receptors were differentially influenced by early life and adult stress in bladder, but not colon, of naïve and NMS mice. Histological evidence of mast cell degranulation was increased in NMS bladder, while protein levels of protease activated receptor 2 (PAR2) and transient receptor potential ankyrin 1 (TRPA1) were increased by WAS. Together, this study provides new insight into mechanisms contributing to stress associated symptom onset or exacerbation in patients exposed to early life stress.

Voluntary wheel running attenuates urinary bladder hypersensitivity and dysfunction following neonatal maternal separation in female mice

“…Here we observed improvements following voluntary exercise on previously established outcomes of NMS in female mice. Sedentary adult female NMS mice developed significant bladder hypersensitivity measured as increased VMR during UBD at 8 weeks of age.…”

“…Dysregulation of the hypothalamic‐pituitary‐adrenal (HPA) axis is a common outcome following exposure to stress or adversity in early life . Rodent models of neonatal maternal separation (NMS) have recapitulated this effect in a laboratory setting, including our studies demonstrating urogenital hypersensitivity in both male and female NMS mice.…”

Lesions of the central amygdala and ventromedial medulla reduce bladder hypersensitivity produced by acute but not chronic foot shock

“…Thus, SIH rather than SIA, is the rule rather than the exception when dealing with visceral disorders. Most of the visceral work on SIH has focused on irritable bowel syndrome and colon hypersensitivity (Zhou and Gebhart, 2002) but a few recent studies have examined substrates of stress-induced exacerbation of urinary bladder hypersensitivity (Black et al, 2009; Robbins et al, 2008, 2007; Smith, 2011, Pierce et al, 2016; Lee et al, 2015). …”

The role of C‐fibers in the development of chronic psychological stress induced enhanced bladder sensations and nociceptive responses: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study

“…VMR is the contraction of the abdominal muscles reflexively activated by visceral stimuli. VMR is a reliable and reproducible marker and its application for visceral sensation measurement has been supported in several previous studies . It can be quantified by determining the vigor of the muscle contraction.…”

“…The WAS‐induced bladder hypersensitivity is similar to other reports regarding different stress animal models. For instance, neonatal maternal separation stress induces bladder hypersensitivity in female mice, which is further exacerbated in adult individuals exposed to WAS . Similarly, a 7‐day exposure to footshock treatments produces bladder hypersensitivity .…”