Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

Abstract

Merrill L, Malley S, Vizzard MA. Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression. Am J Physiol Regul Integr Comp Physiol 305: R147-R156, 2013. First published May 8, 2013 doi:10.1152/ajpregu.00089.2013.-Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were significantly (P Յ 0.01) attenuated by day 5 of RVS, and adrenal weight was significantly (P Յ 0.05) increased. Histamine, MPO, NGF, and CXCL12 protein expression was significantly (P Յ 0.01) increased in the urinary bladder after RVS. Somatic sensitivity of the hindpaw and pelvic regions was significantly (P Յ 0.01) increased at all monofilament forces tested (0.1-4 g) after RVS. Intercontraction interval, infused volume, and void volume were significantly (P Յ 0.01) decreased after RVS. These studies demonstrate increased voiding frequency, histamine, MPO, NGF, and CXCL12 bladder content and somatic sensitivity after RVS suggesting an inflammatory component to stress-induced changes in bladder function and somatic sensitivity. micturition; stress; nerve growth factor; ELISA; somatic sensitivity STRESS CONTRIBUTES to symptom exacerbation in many disease states, including functional disorders of the urinary bladder such as overactive bladder (OAB) and interstitial cystitis (IC)/ bladder pain syndrome (BPS) (3,38,58,72). Urinary frequency is a common symptom among patients with OAB or IC/BPS, although the end result of frequent voiding may differ [reduce incontinence episodes (OAB) vs. reduce pain with bladder filling (IC/BPS)]. Patients with IC/BPS report symptom worsening during stress, as do patients with other disorders associated with IC/BPS including rheumatoid arthritis, psoriasis, and irritable bowel syndrome (47,72). Symptom worsening during stress may be due, in part, to disruption of the hypothalamic-pituitary-adrenal (HPA) axis. Cortisol, through feedback on the HPA axis, normally acts to attenuate inflammation (47); however, abnormalities in the feedback may cause dysregulation of the inflammatory response. Therefore, patients...

Intravesical TRPV4 blockade reduces repeated variate stress-induced bladder dysfunction by increasing bladder capacity and decreasing voiding frequency in male rats

“…The present studies confirmed our recent description (37) that RVS in male rats produces urinary bladder dysfunction characterized by decreased bladder capacity and void volume and increased voiding frequency. Furthermore, these studies demonstrated several novel findings with respect to TRPV4 channel expression in the urinary bladder and the effects of pharmacological manipulation following RVS on urinary bladder function.…”

“…We also demonstrated that RVS produces bladder dysfunction in rats characterized by decreased bladder capacity, intercontraction interval, and void volume (37). These results were confirmed in the present experiments (Table 1).…”

“…Previous work in our laboratory established that RVS produces biological markers of stress similar to other studies (17,18,24,43) including a robust and reproducible reduction (10%) in body weight gain during stressor exposure (37). We also demonstrated that RVS produces bladder dysfunction in rats characterized by decreased bladder capacity, intercontraction interval, and void volume (37).…”

“…A repeated variate stress (RVS) paradigm (17) that lacks habituation was used, in which a different stressor was presented every day for 7 days (d). RVS altered micturition reflex function by causing a decrease in bladder capacity and void volume and an increase in urinary frequency in rats exposed to the RVS paradigm (37). We also observed an increase in nerve growth factor (NGF) protein expression in the urinary bladders of rats exposed to RVS.…”

“…Previous studies in our laboratory have examined stressinduced effects on micturition reflex function (37). A repeated variate stress (RVS) paradigm (17) that lacks habituation was used, in which a different stressor was presented every day for 7 days (d).…”