Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study

PLOS ONE, Nov 2019

Stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitive syndromes, such as interstitial cystitis/bladder pain syndrome (IC/BPS), characterized by urinary frequency and bladder hyperalgesia and heightened stress responsiveness. Given the overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function, as well as its effects on regional brain activation during bladder filling. Female Wistar-Kyoto rats were exposed to WAS (10 days) or sham paradigms. One day thereafter, cystometrograms were obtained during titrated bladder dilation, with visceromotor responses (VMR) recorded simultaneously. Cerebral perfusion was assessed during passive bladder distension (20-cmH2O) following intravenous administration of [14C]-iodoantipyrine. Regional cerebral blood flow was quantified by autoradiography and analyzed in 3-dimensionally reconstructed brains with statistical parametric mapping. WAS animals compared to controls demonstrated a decreased pressure threshold and visceromotor threshold triggering the voiding phase. At 20-cmH2O, VMR was significantly greater in WAS animals compared to controls. WAS animals showed greater activation in cortical regions of the central micturition circuit, including the posterior cingulate, anterior retrosplenial, somatosensory, posterior insula, orbital, and anterior secondary (“supplementary”) motor cortices, as well as in the thalamus, anterior hypothalamus, parabrachial and Barrington nuclei, and striatum. Seed analysis showed increased functional connectivity of WAS compared to control animals of the posterior cingulate cortex to the pontine parabrachial nucleus; of the Barrington nucleus to the anterior dorsal midline and ventrobasilar thalamus and somatosensory and retrosplenial cortices; and of the posterior insula to anterior secondary motor cortex. Our findings show a visceral hypersensitivity during bladder filling in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency, viscerosensory perception and its relay to motor regions coordinating imminent bladder contraction. Results are consistent with recent findings in patients with interstitial cystitis, suggesting that WAS may serve as an animal model to elucidate the mechanisms leading to viscerosensitive brain phenotypes in humans with IC/BPS.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0182976&type=printable

Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study

September Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study Zhuo Wang 0 1 2 3 Harriet H. Chang 0 1 3 Yunliang Gao 0 1 3 Rong Zhang 0 1 3 Yumei Guo 0 1 2 3 Daniel P. Holschneider 0 1 2 3 Larissa V. Rodriguez 0 1 3 0 Current address: Department of Urology, the Second Xiangya Hospital, Central South University , Changsha, Hunan , China 1 Funding: The work was supported by a MAPP Research Network grant (U01 DK082370) from the National Institutes of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health , NIH 2 Department of Psychiatry and Behavioral Sciences at the University of Southern California, Los Angeles, California, United States of America, 2 Department of Urology at the University of Southern California , Los Angeles, California , United States of America 3 Editor: Yvette Tache, University of California Los Angeles , UNITED STATES - Stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders. Chronic water avoidance stress (WAS) in rodents is a model with high construct and face validity to bladder hypersensitive syndromes, such as interstitial cystitis/ bladder pain syndrome (IC/BPS), characterized by urinary frequency and bladder hyperalgesia and heightened stress responsiveness. Given the overlap of the brain circuits involved in stress, anxiety, and micturition, we evaluated the effects chronic stress has on bladder function, as well as its effects on regional brain activation during bladder filling. Female Wistar-Kyoto rats were exposed to WAS (10 days) or sham paradigms. One day thereafter, cystometrograms were obtained during titrated bladder dilation, with visceromotor responses (VMR) recorded simultaneously. Cerebral perfusion was assessed during passive bladder distension (20-cmH2O) following intravenous administration of [14C]-iodoantipyrine. Regional cerebral blood flow was quantified by autoradiography and analyzed in 3dimensionally reconstructed brains with statistical parametric mapping. WAS animals compared to controls demonstrated a decreased pressure threshold and visceromotor threshold triggering the voiding phase. At 20-cmH2O, VMR was significantly greater in WAS animals compared to controls. WAS animals showed greater activation in cortical regions of the central micturition circuit, including the posterior cingulate, anterior retrosplenial, somatosensory, posterior insula, orbital, and anterior secondary (ªsupplementaryº) motor cortices, as well as in the thalamus, anterior hypothalamus, parabrachial and Barrington nuclei, and striatum. Seed analysis showed increased functional connectivity of WAS compared to control animals of the posterior cingulate cortex to the pontine parabrachial nucleus; of the Competing interests: The authors have declared that no competing interests exist. Barrington nucleus to the anterior dorsal midline and ventrobasilar thalamus and somatosensory and retrosplenial cortices; and of the posterior insula to anterior secondary motor cortex. Our findings show a visceral hypersensitivity during bladder filling in WAS animals, as well as increased engagement of portions of the micturition circuit responsive to urgency, viscerosensory perception and its relay to motor regions coordinating imminent bladder contraction. Results are consistent with recent findings in patients with interstitial cystitis, suggesting that WAS may serve as an animal model to elucidate the mechanisms leading to viscerosensitive brain phenotypes in humans with IC/BPS. Introduction Chronic emotional stress plays a role in the exacerbation and possibly the development of functional lower urinary tract disorders (LUTD) [1±5]. These disorders can be viewed as a spectrum of bladder hypersensitivity syndromes sharing the common symptoms of urinary frequency and urgency, with bladder pain syndrome/interstitial cystitis (IC/BPS) patients experiencing pain as an additional symptom. Work over the past decade in chronic pain disorders, including IC/BPS, irritable bowel syndrome, fibromyalgia and vulvodynia, suggests the presence in these conditions of altered sensory perception [6±8]. Specific to IC/BPS, recent work has shown that patients compared to healthy controls show increased functional brain activation in the full bladder state broadly across sites in brain circuits serving sensory perception and pain [ 9 ]. The possibility of altered central processing of sensory input is paralleled by epidemiologic studies documenting that a substantial number of IC/BPS patients report stressrelated symptom onset and/or severity, difficulty coping with stressful situations, and symptoms of depression, anxiety, and panic disorder [5,10±15]. However, the relationship between chronic stress, bladder function and brain functional responses remains uncle (...truncated)


This is a preview of a remote PDF: https://journals.plos.org/plosone/article/file?id=10.1371/journal.pone.0182976&type=printable

Zhuo Wang, Harriet H. Chang, Yunliang Gao, Rong Zhang, Yumei Guo, Daniel P. Holschneider, Larissa V. Rodriguez. Effects of water avoidance stress on peripheral and central responses during bladder filling in the rat: A multidisciplinary approach to the study of urologic chronic pelvic pain syndrome (MAPP) research network study, PLOS ONE, 2017, Volume 12, Issue 9, DOI: 10.1371/journal.pone.0182976