Loss of purinergic P2X receptor innervation in human detrusor and subepithelium from adults with sensory urgency

Abstract

Purinergic P2X receptors associated with the parasympathetic nerves supplying human bladder smooth muscle (detrusor) are implicated in control of detrusor contractility. The relative abundance of all seven subtypes colocalised with synaptic vesicles on parasympathetic nerves was examined in specimens from normal adult bladder and in adults with the urodynamics findings of sensory urgency (SU) to determine how receptor distribution varied in patients with a small bladder capacity. Alteration in control of detrusor innervation was examined with P2X subtype-specific antibodies and an antibody (SV2) against synaptic vesicles, using immunofluorescence and confocal microscopy. Detrusor samples were taken from: controls, at cystectomy for cancer or cystoscopic biopsy for haematuria (n=22, age 33-88 years) and adults with sensory urgency at cystoscopy/cystodistension (n=11, age 37-70 years). Normal adult specimens contained detrusor muscle innervated by parasympathetic nerves possessing large varicosities (1.2 microm) distributed along their length. These mostly all showed colocalised patches of presynaptic P2X(1,2,3,5) subtypes while presynaptic subtypes P2X(4,6,7) were present in only 6-18% of varicosities. Detrusor nerve varicosities from SU patients revealed general loss of all presynaptic P2X subtypes with the proportion containing receptors reducing to only 0.5-5% depending on P2X subtype. The same loss was recorded from the sensory nerves in the surrounding lamina propria. This specific loss of P2X receptors may impair control of detrusor distension and contribute to the pathophysiology of sensory urgency.

Expression and Distribution of Ectonucleotidases in Mouse Urinary Bladder

“…ATP release from the urothelium is significantly elevated in aging [31], interstitial cystitis [10]–[11], in spinal cord injury [15], during inflammation [14] and in syndromes of detrusor overactivity resulting in urgency and/or incontinence [32]. Furthermore overactive bladder has been shown to broadly downregulate the expression of P2X receptors in detrusor [13], [17] while conversely P2X 3 was upregulated in sensory nerve fibers from patients with neurogenic detrusor overactivity [33]. P2X 3 is also upregulated in a model of outlet obstruction in rats [18] while human patients with outlet obstruction had elevated P2X 1 [19] and P2X 2 [34] receptors in their bladder smooth muscle.…”

“…Furthermore, abnormalities in ATP release and in purinergic receptor expression have been noted in numerous studies of human bladder disease as well as in animal models of bladder pathology. These include interstitial cystitis [10]–[12], urinary urgency and incontinence [13], bladder inflammation [14], spinal cord injury-induced bladder dysfunction [15], detrusor overactivity [16]–[17] and outlet obstruction [18]–[20].…”

Differential purinergic signaling in bladder sensory neurons of naïve and bladder-inflamed mice

“…ATP is released from bladder urothelium during distension or chemical stimulation [17,3] and release is increased in PBS/IC patients [37,38]. Purinergic ionotropic (P2X) receptors have been implicated in bladder overactivity and disorders of sensation in humans [23,30,40] and animals [16,52]. In addition, P2X2, P2X3 and P2X2/P2X3 double knockout mice exhibit reduced bladder reflexes and decreased afferent nerve activity in response to bladder distension [10,9,48].…”

Botulinum toxin injection: a review of injection principles and protocols

“…However, a significant amount of subsequent basic and clinical research has suggested that sensory neuron dysfunction may actually contribute to the pathophysiology of detrusor overactivity, sensory urgency, and IC (35)(36)(37). In addition, increasing evidence suggests that botulinum toxin inhibits both sensory neuron actions and the release of sensory neuropeptides from adjacent cell types (e.g.…”