A ventral root avulsion injury model for neurogenic underactive bladder studies

Abstract

Detrusor underactivity (DU) is defined as a contraction of reduced strength and/or duration during bladder emptying and results in incomplete and prolonged bladder emptying. The clinical diagnosis of DU is challenging when present alone or in association with other bladder conditions such as detrusor overactivity, urinary retention, detrusor hyperactivity with impaired contractility, aging, and neurological injuries. Several etiologies may be responsible for DU or the development of an underactive bladder (UAB), but the pathobiology of DU or UAB is not well understood. Therefore, new clinically relevant and interpretable models for studies of UAB are much needed in order to make progress towards new treatments and preventative strategies. Here, we review a neuropathic cause of DU in the form of traumatic injuries to the cauda equina (CE) and conus medullaris (CM) portions of the spinal cord. Lumbosacral ventral root avulsion (VRA) injury models in rats mimic the clinical phenotype of CM/CE injuries. Bilateral VRA injuries result in bladder areflexia, whereas a unilateral lesion results in partial impairment of lower urinary tract and visceromotor reflexes. Surgical re-implantation of avulsed ventral roots into the spinal cord and pharmacological strategies can augment micturition reflexes. The translational research need for the development of a large animal model for UAB studies is also presented, and early studies of lumbosacral VRA injuries in rhesus macaques are discussed.

Keywords: And conus medullaris; Cauda equine; Electromyography; External urethral sphincter; Serotonin; Spinal cord injury.

Fig. 1

Anatomical schematics showing the avulsion injury of L5-S2 ventral roots from the surface of the spinal cord (A), and re-implantation of avulsed L6-S1 ventral roots into the lateral funiculus of the spinal cord (B).

Fig. 2

The bladder wall thickness is reduced in rats after a lumbosacral VRA injury and is partially restored after an acute implantation of avulsed ventral roots into the CM. The whole bladder wall thickness (A) was measured as was the thickness of the epithelium (B), lamina propria (C) and smooth muscle (D) layers in rats of the sham, VRA and re-implanted series; * indicates p<0.05. Reprinted from (Chang and Havton, 2008b) with permission from Elsevier.

Fig. 3

Urodynamic recordings obtained from the sham rat (A-C) and a rat with unilateral L5-S2 VRA injury (D-F). Top tracings demonstrate the intravesical bladder pressure and continuous voiding contractions evoked by saline infusion. Middle and bottom tracings show the EUS EMG activity from ipsilateral and contralateral sides, respectively, associated with voiding contractions. Drug administrations of 8-OH-DPAT were intravenously given at the dosages of 0.3 and 1.0 mg/kg. The generation of this new figure was based on unpublished traces collected from data sets generated for our previous publication (Chang and Havton, 2013). The upper right corners at sham (A) and VRA (D) rats showed the faster time of EUS bursting (1-second period) at ipsilateral side, where the asterisks indicated the voiding contractions, before administration of 8-OH-DPAT.

Fig. 4

Bladder intravesical and urethral pressures were recorded from a neurologically intact female rhesus macaque (A) and after a unilateral lumbosacral VRA injury (B). The saline was infused at the rate of 15-30 mL per minute. A total volume of 180 mL was infused in each subject to partially fill the bladder and facilitate the voiding responses. Urethral pressure was used to indicate the duration of urine expulsion. In the control subject (A), the bladder intravesical pressure was higher during voiding and generated 68 mL of urine by a continuous flow. The subject after a unilateral lumbosacral VRA injury (B) presented the intermittent voiding and voided 41 mL of urine.