Molecular Mechanisms of Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury

Abstract

This article provides a synopsis of current progress made in fundamental studies of lower urinary tract dysfunction (LUTD) after spinal cord injury (SCI) above the sacral level. Animal models of SCI allowed us to examine the effects of SCI on the micturition control and the underlying neurophysiological processes of SCI-induced LUTD. Urine storage and elimination are the two primary functions of the LUT, which are governed by complicated regulatory mechanisms in the central and peripheral nervous systems. These neural systems control the action of two functional units in the LUT: the urinary bladder and an outlet consisting of the bladder neck, urethral sphincters, and pelvic-floor striated muscles. During the storage phase, the outlet is closed, and the bladder is inactive to maintain a low intravenous pressure and continence. In contrast, during the voiding phase, the outlet relaxes, and the bladder contracts to facilitate adequate urine flow and bladder emptying. SCI disrupts the normal reflex circuits that regulate co-ordinated bladder and urethral sphincter function, leading to involuntary and inefficient voiding. Following SCI, a spinal micturition reflex pathway develops to induce an overactive bladder condition following the initial areflexic phase. In addition, without proper bladder–urethral-sphincter coordination after SCI, the bladder is not emptied as effectively as in the normal condition. Previous studies using animal models of SCI have shown that hyperexcitability of C-fiber bladder afferent pathways is a fundamental pathophysiological mechanism, inducing neurogenic LUTD, especially detrusor overactivity during the storage phase. SCI also induces neurogenic LUTD during the voiding phase, known as detrusor sphincter dyssynergia, likely due to hyperexcitability of Aδ-fiber bladder afferent pathways rather than C-fiber afferents. The molecular mechanisms underlying SCI-induced LUTD are multifactorial; previous studies have identified significant changes in the expression of various molecules in the peripheral organs and afferent nerves projecting to the spinal cord, including growth factors, ion channels, receptors and neurotransmitters. These findings in animal models of SCI and neurogenic LUTD should increase our understanding of pathophysiological mechanisms of LUTD after SCI for the future development of novel therapies for SCI patients with LUTD.

Incidence and risk factors of urinary tract infection in hospitalized patients with spinal cord injury in a hospital of China

“…In this study, the prevalence of urinary incontinence in Chinese patients with SCI was as high as 19.9% (n = 107). Urinary incontinence in patients with SCI is often caused by overactivity of the forced urinary muscles 30 . Overactivity of the detrusor muscle may lead to mucosal ischemia, and inadequate tissue perfusion affecting the natural protection of the mucosa by blood and reducing the release of inflammatory cells, thus promoting the proliferation of microorganisms 31 .…”

Improvement of lower urinary tract dysfunction by a monoacylglycerol lipase inhibitor in mice with spinal cord injury

“…Previous studies have shown that TRP channels such as TRPA1 and TRPV1, which are predominantly expressed in C-fiber afferent neurons, are upregulated in L6-S1 DRG or the bladder mucosa in animal models of SCI-induced LUTD and that C-fiber bladder afferent hyperexcitability contributes to DO in animal models of SCI. 18 Moreover, it has been demonstrated that activation of CB1 receptors by the intravesical instillation of a CB1 agonist or by the reduction of degradation of endocannabinoids in FAAH knockout mice suppressed bladder activity enhanced by nerve growth factor. 19 Moreover, CB2 receptor stimulation by a CB2 agonist reportedly inhibited the mechanosensitivity of bladder mucosal capsaicin-sensitive C-fiber afferents in the organ bath study.…”

Assessing Neurogenic Lower Urinary Tract Dysfunction after Spinal Cord Injury: Animal Models in Preclinical Neuro-Urology Research

“…Small rodents, such as rats and mice, have formed the foundation of our understanding of the neural control of micturition and the mechanisms underlying the impairment of LUT function after SCI, in part because their bladders have been well-characterized by both in vitro and in vivo experiments [ 20 , 123 , 142 , 143 , 144 , 145 ]. Their lifespan of about 1–2 years means that it is also feasible to evaluate the effects of chronic SCI [ 118 ].…”

“…Moreover, the quantitative observation of urinary tract function before and after SCI—in the same individual—is effectively impossible with human patients. Animal models are therefore critical for investigating the in vivo consequences of NLUTD, and they allow for the development and testing of novel therapeutic approaches and understanding the complex pathophysiology of a neurogenic bladder [ 20 ]. Given the importance of animal models, clinical UDS has been adapted to a wide variety of animal species.…”