Activation and sensitisation of low and high threshold afferent fibres mediated by P2X receptors in the mouse urinary bladder

Abstract

It has been proposed that extracellular ATP may be involved in visceral mechanosensory transduction by activating ligand‐gated ion channels (P2X receptors). In this study, we have investigated the effects of the P2X3 agonist α,β‐methylene ATP (α,β‐meATP) and antagonist 2′,3′‐O‐trinitrophenyl‐ATP (TNP‐ATP) on pelvic afferents innervating the urinary bladder using an in vitro mouse bladder‐pelvic nerve preparation. Intravesical application of α,β‐meATP (0.03‐1 mm) increased multifibre discharges in a concentration‐dependent manner. The agonist potentiated, whereas TNP‐ATP (0.03 mm) attenuated, the multifibre responses to bladder distensions. Single‐unit analysis revealed that both high threshold (HT) fibres (> 15 mmHg; known to be associated with nociception) and low threshold (LT) fibres (< 15 mmHg; probably associated with non‐nociceptive events) could be induced to discharge by intravesical α,β‐meATP (1 mm, 0.1 ml). The response of the vast majority (21/22, 95.5 %) of HT fibres to bladder distensions was enhanced with a significantly reduced threshold and an increased peak response after exposure to the agonist. On the other hand, 59.7 % (46/77) of LT fibres showed a greater peak and a slightly reduced threshold for response to bladder distension in the presence of α,β‐meATP. An additional 11 ‘silent’ fibres became mechanosensitive after exposure to α,β‐meATP. TNP‐ATP (0.03 mm) did not affect the threshold of LT fibres, but it reduced the peak response of some (22/51, 43.1 %) LT fibres. Conversely, the antagonist resulted in a markedly elevated threshold and reduced peak activity in the majority (13/16, 81.3 %) of HT fibres. The results support the view that P2X3 receptor‐mediated mechanisms contribute to both nociceptive and non‐nociceptive (physiological) mechanosensory transduction in the urinary bladder.

Cyclophosphamide-Induced Bladder Inflammation Sensitizes and Enhances P2X Receptor Function in Rat Bladder Sensory Neurons

“…The altered P2X receptor expression accounts for greater current density in response to purinergic agonists, and likely contributes to the slowed desensitization kinetics of the slow desensitizing current after bladder inflammation. Considering the reported mechanosensory role for homomeric P2X 3 and P2X 2 and heteromeric P2X 2/3 receptors (Cockayne et al 2000(Cockayne et al , 2005Rong et al 2002;Vlaskovska et al 2001), and the increased urothelial release of ATP during inflammation (Sun et al 2001), the present findings suggest that the altered expression of P2X receptors contributes to the enhanced responses of bladder neurons during cystitis.…”

Effect of electroacupuncture on P2X3 receptor regulation in the peripheral and central nervous systems of rats with visceral pain caused by irritable bowel syndrome

“…Using experiments, Burnstock demonstrated that when a hollow viscus (such as the intestine, ureter, and bladder) was extensively distended and overfilled, the epithelial cells in the cavity would be stimulated to release ATP, which would subsequently activate the P2X 3 and P2X 2/3 receptors in the subepithelial nerve endings to generate action potentials [25]; this change corresponds to hyperexcitability of the sensory neurons, and the action potentials would be transmitted to the central nervous system, resulting in a colicky sensation [26,27]. In this study, the method of colorectal balloon distention was used to prepare an animal model of IBS visceral hyperalgesia in rats, and the expression of the P2X 3 receptor in the colon myenteric plexus of the rats in the IBS model group was found to be higher than that of the rats in the normal group.…”

Detrusor overactivity induced by intravesical application of adenosine 5′-triphosphate under different delivery conditions in rats

“…In our study, when DIDS, an inhibitor of ecto-ATPase 13 , was infused intravesically, the following application of ATP (pH 6.0) induced detrusor overactivity without pre-infusion of PS. Rong et al also showed that intravesical application of α,β-methylene ATP increased multifiber discharges in the mouse bladder, suggesting that α,β-methylene ATP can penetrate the urothelium 14 . Taken together, it is assumed that ATP (pH 6.0) with co-application of DIDS or α,β-methylene ATP can penetrate bladder epithelium to induce detrusor overactivity without changing urothelial permeability and that, in addition to urothelial barrier function, ecto-ATPase activity in the urothelium also contributes to the suppression of ATP-induced detrusor overactivity.…”