Role of p38 MAP kinase signaling pathways in storage and voiding dysfunction in mice with spinal cord injury

Abstract

Aim: To investigate the role of p38 MAP kinase in lower urinary tract dysfunction in mice with spinal cord injury (SCI). Methods: Cystometry and external urethral sphincter-electromyography were performed under an awake condition in 4-week SCI female mice. Two weeks after SCI, a catheter connected to an osmotic pump filled with a p38 mitogen-activated protein kinase (MAPK) inhibitor or artificial cerebrospinal fluid (CSF) was implanted into the intrathecal space of L6-S1 spinal cord for continuous intrathecal instillation at infusion rate of 0.51 μL/h for 2 weeks before the urodynamic study. L6 dorsal root ganglia were then removed from CSF and p38 MAPK inhibitor-treated SCI mice as well as from CSF-treated normal (spinal intact) mice to evaluate the levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) transcripts by real-time polymerase chain reaction.Results: In p38 MAPK inhibitor-treated SCI mice, nonvoiding contractions during bladder filling, bladder capacity, and post-void residual volume were significantly reduced while micturition pressure and voiding efficiency were significantly increased in comparison to these measurements in CSF-treated SCI mice. The expression of TRPV1, TNF-α, and iNOS messenger RNA was increased in SCI mice compared with expression in spinal intact mice and significantly decreased after p38 MAPK inhibitor treatment. Conclusions:The p38 MAPK signaling pathway in bladder sensory neurons or in the spinal cord plays an important role in storage and voiding problems such as detrusor overactivity and inefficient voiding after SCI. K E Y W O R D Sdetrusor overactivity, mice, p38 MAP kinase, spinal cord injury, urodynamics

Sex differences in lower urinary tract function in mice with or without spinal cord injury

“…It has been reported that anti‐NGF treatment with NGF antibodies significantly decreased NVCs in SCI female mice 18 . Furthermore, it has been demonstrated that SCI‐induced detrusor overactivity is induced at least in part by hyperexcitability of C‐fiber bladder afferent pathways and that increased levels of TRPV1, which is predominantly expressed in C‐fiber bladder afferent neurons in L6‐S1 DRG, are involved in C‐fiber afferent hyperexcitability following SCI 4,19,20 . However, the current study did not show any significant differences in TRPV1 in L6‐S1 DRG or NGF‐β levels in the bladder between male and female SCI mice while higher numbers of NVCs were observed in male SCI mice than in female SCI.…”

“…18 Furthermore, it has been demonstrated that SCI-induced detrusor overactivity is induced at least in part by hyperexcitability of C-fiber bladder afferent pathways and that increased levels of TRPV1, which is predominantly expressed in C-fiber bladder afferent neurons in L6-S1 DRG, are involved in C-fiber afferent hyperexcitability following SCI. 4,19,20 However, the current study did not show any significant differences in TRPV1 in L6-S1 DRG or NGF-β levels in the bladder between male and female SCI mice while higher numbers of NVCs were observed in male SCI mice than in female SCI. Thus, this sex difference in detrusor overactivity might be related to other factors, for example, bladder ischemia due to bladder outlet obstruction in male SCI mice 21 although further studies need to be performed to clarify this point.…”

“…SI and SCI female mice urinated during reduced EUS-EMG activity that reflects EUS relaxation as reported in previous studies. 4,17 Thus, in comparison to male SCI mice, female SCI mice, which exhibit DSD with periodic EUS relaxations, seem to be more suitable models of human SCI-induced EUS dysfunction where voiding also occurs during EUS relaxation periods. Plasticity in primary afferent pathways may contribute to LUTD after SCI.…”

“…Lower urinary tract dysfunction (LUTD) significantly reduces quality of life in both sexes 1,2 . The majority of previous basic research investigations on the mechanisms of LUTD after spinal cord injury (SCI) were predominantly performed using female rodents 3–5 . In addition, there have been no studies of bladder and urethral coordination in male mice although several researchers have suggested that there are sex differences in the urethra, in terms of its function, morphology, and distribution of receptors such as α1‐adrenoceptors and hormonal receptors 6–8 .…”

“…1,2 The majority of previous basic research investigations on the mechanisms of LUTD after spinal cord injury (SCI) were predominantly performed using female rodents. [3][4][5] In addition, there have been no studies of bladder and urethral coordination in male mice although several researchers have suggested that there are sex differences in the urethra, in terms of its function, morphology, and distribution of receptors such as α1adrenoceptors and hormonal receptors. [6][7][8] It has been shown that male and female rats exhibit bursting activity of the external urethral sphincter (EUS) during voiding, which acts as urethral pumping function to help efficient voiding.…”