Does ketamine ameliorate the social stress‐related bladder dysfunction in mice?

Abstract

Aims The aim of this study is to investigate whether ketamine could relieve the social stress (SS)‐related bladder dysfunction in mice. Materials and Methods The FVB mice were randomly assigned to either undergo SS exposure for 60 minutes per day on seven consecutive days for 4 weeks (SS1) or control without SS (SS0). The SS0 were then allocated to single or no injection of ketamine (SS0K1 and SS0K0). In the group of SS1, the SS1 mice were allocated to receive single injection of saline (SS1K0), single dose (SS1K1) or five daily dose of (SS1K5) ketamine injection (25 mg/kg/day/ip) since day 22. In vivo cystometry and tissue bath wire myography were performed on day 29. Serum and urine level of brain‐derived neurotrophic factor (BDNF) were measured with enzyme‐linked immunosorbent assay. Results In mice without social stress exposure, ketamine administration did not significantly affect voiding frequency (P > .05). SS1K0, SS1K1, and SS1K5 had significantly lower voiding frequency than that of control (SS1K0) (each n = 15, P < .05). Ketamine administration reversed the trend of decreased voiding frequency in SS1 mice. Stressed mice had significant higher serum level of BDNF that reduced by short‐term ketamine. Stressed mice had detrusor overactivity and impaired detrusor contractility which were not reversed by short‐term ketamine. Conclusions Social stress leads to elevated serum BDNF, infrequent voiding, detrusor overactivity, and impaired contractility. Short‐term administration of ketamine may improve SS‐related infrequent voiding and elevated serum BDNF level. However, ketamine did not improve SS‐related bladder dysfunction on urodynamic and myography studies.

The Effect of Chronic Psychological Stress on Lower Urinary Tract Function: An Animal Model Perspective

“…This could be exemplified by Chang et al’s study, in which a single submissive FVB mouse was repeatedly exposed (4 weeks) to an aggressive male C57BL/6 mouse for 1 h a day followed by 23 h of barrier separation ( Chang et al, 2009 ). Several other investigators conducted similar paradigms to induce social stress ( Long et al, 2014 ; Mingin et al, 2014 , 2015 ; Weiss et al, 2015 ; Yang et al, 2020 ). Alternatively, the duration of social stress in the study Mann et al (2015) was reduced to 2 weeks, and the direct daily exposure of male mice to aggressive ones was reduced to 10 min.…”

“…Administration of a CRF1 antagonist or shRNA targeting CRF in Barrington’s nucleus could improve social stress-induced retention ( Wood et al, 2013 ). Another elevated neuropeptide brain-derived neurotrophic factor was also noted in rodent serum after social stress exposure, and a short-term subanesthetic dose of ketamine reduced its expression and reverse the trend of stress-related infrequent voiding ( Yang et al, 2020 ).…”

“…These animal models appear to share multiple key characteristics of LUTDs such as increased voiding frequency ( Smith et al, 2011 ), enhanced bladder pain ( Lee et al, 2015 ), or bladder distension ( Chang et al, 2009 ). Currently, a substantial number of animal models have been developed to study stress-induced LUTD, and the commonly used models include water avoidance stress (WAS) ( Cetinel et al, 2005 ; Saglam et al, 2006 ; Robbins et al, 2007 ; Zeybek et al, 2007 ; Okasha and Bayomy, 2010 ; Smith et al, 2011 ; McGonagle et al, 2012 ; Yamamoto et al, 2012 ; Bazi et al, 2013 ; Lee et al, 2015 ; Ackerman et al, 2016 ; Gao et al, 2017 ; Matos et al, 2017 ; Dias et al, 2019 ; Kullmann et al, 2019 ; Holschneider et al, 2020a , b ; Sanford et al, 2020 ; West et al, 2021 ), social stress ( Chang et al, 2009 ; Wood et al, 2009 , 2012 , 2013 ; Mann et al, 2015 ; Mingin et al, 2015 ; Weiss et al, 2015 ; Wang et al, 2017 ; Butler et al, 2018 ; West et al, 2020 ; Yang et al, 2020 ), early life stress (ELS) ( Chaloner and Greenwood-Van Meerveld, 2013 ; Mohammadi et al, 2016 ; Pierce et al, 2016 , 2018 ; Fuentes et al, 2017 , 2021 ; Fuentes and Christianson, 2018 ; Ligon et al, 2018 ), and repeated variable stress (RVS) ( Hammack et al, 2009 ; Merrill et al, 2013 ; Merrill and Vizzard, 2014 ; Hattori et al, 2019 ; Girard et al, 2020 ). As shown by the findings from these models, chronic stress could induce functional and histopathological changes at multiple levels of the micturition pathway, providing insight into the underlying mechanisms and potential treatments of LUTD.…”

Psychological/mental stress‐induced effects on urinary function: Possible brain molecules related to psychological/mental stress‐induced effects on urinary function

“…2,36 Mice exposed to repeated SDS (1 h daily for 28 consecutive days) also showed increased bladder mass, VV and the number of NVCs, and decreased urinary frequency. [37][38][39] The SDS-induced voiding postponement in rodents might model dysfunctional voiding and be linked to childhood physical or sexual abuse in humans. 3,40,41 Furthermore, repeated exposure to SDS upregulated CRF, a stressrelated neuropeptide that centrally activates the sympathetic nerves and the HPA axis, 42 in neurons of Barrington's nucleus (pontine micturition center) in rats and mice, 2,36,38 and pretreatment with CRF receptor antagonist improved the SDS-induced increases in BC, micturition volume and ICI in rats.…”

“…The repeated SDS induced urinary retention with increased ICI, BC, micturition volume and the number of NVCs in rats 2,36 . Mice exposed to repeated SDS (1 h daily for 28 consecutive days) also showed increased bladder mass, VV and the number of NVCs, and decreased urinary frequency 37–39 . The SDS‐induced voiding postponement in rodents might model dysfunctional voiding and be linked to childhood physical or sexual abuse in humans 3,40,41 .…”