Botulinum Neurotoxin Serotype A Suppresses Neurotransmitter Release from Afferent as Well as Efferent Nerves in the Urinary Bladder

Background: Botulinum neurotoxin A (BoNTA), which alleviates overactive bladder symptoms, is thought to act predominantly via the inhibition of transmitter release from parasympathetic nerves. However, actions at other sites such as afferent nerve terminals are possible. Objective: To evaluate the effects of BoNTA on bladder afferent neuropeptide release and firing. Design, setting, and participants: One side of the bladder of control and chronic (1-2 wk) spinal cord transected (SCT; T-8-T-9) adult female mice was injected with BoNTA (0.5 U/5 mu l saline). After 48 h, bladders with L-6-S-2 spinal nerves were prepared for in vitro recordings. Outcome measurements and statistical analysis: In bladder preparations, tension and optical mapping of Ca2+ transients were used to measure intrinsic contractions, those evoked by capsaicin or the electrical stimulation of spinal nerves. Afferent firing was evoked by stretch or intrinsic bladder contractions. The numbers of responding units and firing rates were measured. Animal numbers were used to detect moderate to large between-group differences based on Cohen's criteria. Two-way analysis of variance was used to test spatial/temporal differences in Ca2+ signals as mean plus or minus standard deviation. Differences between data sets were tested with the student t test and skewed data sets with a Mann-Whitney U test (significant when p < 0.05). Results and limitations: In control and SCT bladders, BoNTA treatment decreased the contractions evoked by electrical stimulation of spinal nerves without altering intrinsic contractions. Afferent firing on untreated sides in response to stretch/intrinsic contractions was increased in SCTs versus controls. On BoNTA-treated sides, afferent firing rates were greatly attenuated in response to mechanical stimulation as were the capsaicin-evoked optical signals mediated by neuropeptide release. Conclusions: SCT caused an increased sensitivity of afferent nerves to mechanical stimulation that was reduced by BoNTA treatment. Increased intrinsic activity after SCT was unaffected by the toxin. Thus BoNTA suppresses neurogenic detrusor overactivity by targeting afferent as well as efferent pathways in the bladder. (C) 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.