Urothelial cell activation leads to afferent excitability: Effects of botulinum toxin A

Abstract

Targeting urothelial (UT) release mechanisms may prove important in treatment in a number of bladder dysfunctions. For example, a number of studies demonstrate the therapeutic benefit of botulinum toxin serotype A (BoNTA) in the treatment for neurogenic and non-neurogenic detrusor overactivity. Use of botulinum toxins inhibits release of transmitters (such as Ach or ATP) from a variety of nerve cells. In the urinary bladder, the effectiveness of BoNTA (administered by injection into bladder muscle) is thought to be due to a block of transmitters released from bladder nerves. We have previously shown that BoNTA may also block release of mediators (ATP) from non-neural cells (UT cells). Given that factors (such as ATP) released from UT cells could modulate bladder function, the goals of this study were to examine whether intravesical administration of BoNTA (10nM) can decrease release of ATP from urothelium. Intravesical acetic acid (AA; 0.5%) releases ATP (measured from luciferase method) as does mechanical stretch. Preincubation with intravesical BoNTA (10nM) prior to AA infusion significantly decreases both stretch (83.9%) and AA (73.2%) induced release of ATP. We have shown that intravesical AA induces c-fos expression in spinal cord neurons to which bladder afferents project. We now show that BoNTA also reduces the AA induced c-fos in spinal cord regions (AA, 59.8 cells/section; AA+BoNTA, 1.8 cells/section) which receive input from nociceptive afferents. These findings suggest that targeting UT cell release mechanisms may be important in a number of bladder disorders. This study was supported by NIH DKR0154824.