Targeting the visceral purinergic system for pain control

Experimental evidence is presented to support the hypothesis that purinergic mechanosensory transduction can initiate visceral pain in urinary bladder, ureter, gut and uterus. In general, physiological reflexes are mediated via P2X3 and P2X2/3 receptors on low threshold sensory fibres, while these receptors on high threshold sensory fibres mediate pain. Potential therapeutic strategies are considered for the treatment of visceral pain in such conditions as renal colic, interstitial cystitis and inflammatory bowel disease by purinergic agents, including P2X3 and P2X2/3 receptor antagonists that are orally bioavailable and stable in vivo and agents that modulate ATP release and breakdown.

► Distension of visceral tubes and sacs, including urinary bladder, ureter and gut, is associated with pain. ► P2X3 homomultimer and P2X2/3 heteromultimer nucleotide receptors are located on sensory nerve terminals in visceral organs. ► Distension releases ATP from urothelium to act on subepithelial P2X3 or P2X2/3 receptors initiating nociception. ► Supporting evidence includes increased sensory nerve activity with distension mimicked by ATP, blocked by P2X3 antagonists. ► In colitis models increased responses to ATP are associated with expression of P2X3 receptors on more CGRP DRG neurons.