Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity.
OBJECTIVE
Botulinum neurotoxin type A (BoNT/A) is effective in the treatment of intractable detrusor overactivity (DO). In addition to its known inhibitory effect on presynaptic release of acetylcholine by motor terminals, there is increasing evidence that BoNT/A may affect sensory fibers. We investigated a possible effect of BoNT/A on human bladder afferent mechanisms by studying the sensory receptors P2X3 and TRPV1 in biopsies from patients with neurogenic or idiopathic DO.


METHODS
A total of 38 patients (22 with neurogenic DO, 16 with idiopathic DO) with intractable DO were treated with intradetrusor BoNT/A, and bladder biopsies were taken at 4 and 16 weeks. Urodynamics and voiding diary were also recorded. Specimens were studied immunohistochemically for P2X3, TRPV1 and the pan-neuronal marker PGP9.5, in comparison with controls.


RESULTS
P2X3-immunoreactive and TRPV1-immunoreactive (-IR) fibers were decreased at 4 weeks after BoNT/A, and more significantly at 16 weeks (paired t test p=0.0004 and p=0.0008, respectively), when significant improvements were observed in clinical and urodynamic parameters. P2X3-IR fiber decrease was significantly correlated with reduction of urgency episodes at 4 and 16 weeks (p=0.0013 at 4 weeks and p=0.02 at 16 weeks), but not maximum cystometric capacity or detrusor pressures. TRPV1-IR fiber decrease showed a similar trend. PGP9.5-IR suburothelial fibers remained unchanged after treatment at both followups (p=0.85 and p=0.21 at 4 and 16 weeks, respectively). Urothelial cell P2X3-IR and TRPV1-IR also appeared unchanged.


CONCLUSIONS
Decreased levels of sensory receptors P2X3 and/or TRPV1 may contribute to the clinical effect of BoNT/A in detrusor overactivity.
Apostolidis
A
A
Peripheral Neuropathy Unit, Hammersmith Hospital, Imperial College London, United Kingdom.
Popat
R
R
Yiangou
Y
Y
Cockayne
D
D
Ford
A P D W
AP
Davis
J B
JB
Dasgupta
P
P
Fowler
C J
CJ
Anand
P
P
D000328:Adult; D000344:Afferent Pathways / Q000187:drug effects; D000368:Aged; D001706:Biopsy; D019274:Botulinum Toxins, Type A / Q000008:administration & dosage* / Q000009:adverse effects; D003558:Cystoscopy; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007273:Injections, Intramuscular; D007473:Ion Channels / Q000187:drug effects*; D008297:Male; D008875:Middle Aged; D009122:Muscle Hypertonia / Q000188:drug therapy* / Q000473:pathology; D009412:Nerve Fibers / Q000187:drug effects* / Q000473:pathology; D036421:Nerve Fibers, Unmyelinated / Q000187:drug effects / Q000473:pathology; D009465:Neuromuscular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D018048:Receptors, Purinergic P2 / Q000187:drug effects*; D058477:Receptors, Purinergic P2X3; D012680:Sensitivity and Specificity; D011984:Sensory Receptor Cells / Q000187:drug effects*; D009435:Synaptic Transmission / Q000187:drug effects*; D050916:TRPV Cation Channels; D016896:Treatment Outcome; D001743:Urinary Bladder / Q000294:innervation* / Q000473:pathology; D001750:Urinary Bladder, Neurogenic / Q000188:drug therapy* / Q000473:pathology; D014549:Urinary Incontinence / Q000188:drug therapy* / Q000473:pathology; D014563:Urodynamics / Q000187:drug effects; D019459:Urothelium / Q000294:innervation / Q000473:pathology
D007473:Ion Channels; D009465:Neuromuscular Agents; C546407:P2RX3 protein, human; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D019274:Botulinum Toxins, Type A