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The Journal of Neuroscience, August 1, 2001, 21(15):5670-5677

P2X₃ Knock-Out Mice Reveal a Major Sensory Role for Urothelially Released ATP

Mila Vlaskovska¹, Lubomir Kasakov¹, Weifang Rong¹, Philippe Bodin¹, Michelle Bardini¹, Debra A. Cockayne², Anthony P. D. W. Ford², and Geoffrey Burnstock¹

¹ Autonomic Neuroscience Institute, Royal Free and University College Medical School, London NW3 2PF, United Kingdom, and ² Roche Bioscience, Palo Alto, California 94304

The present study explores the possible involvement of a purinergic mechanism in mechanosensory transduction in the bladder using P2X₃ receptor knock-out (P2X₃^/) and wild-type control (P2X₃^+/+) mice. Immunohistochemistry revealed abundant nerve fibers in a suburothelial plexus in the mouse bladder that are immunoreactive to anti-P2X₃. P2X₃-positive staining was completely absent in the subepithelial plexus of the P2X₃^/ mice, whereas staining for calcitonin gene-related peptide and vanilloid receptor 1 receptors remained. Using a novel superfused mouse bladder-pelvic nerve preparation, we detected a release of ATP proportional to the extent of bladder distension in both P2X₃^+/+ and P2X₃^/ mice, although P2X₃^/ bladder had an increased capacity compared with that of the P2X₃^+/+ bladder. The activity of multifiber pelvic nerve afferents increased progressively during gradual bladder distension (at a rate of 0.1 ml/min). However, the bladder afferents from P2X₃^/ mice showed an attenuated response to bladder distension. Mouse bladder afferents of P2X₃^+/+, but not P2X₃^/, were rapidly activated by intravesical injections of P2X agonists (ATP or ,-methylene ATP) and subsequently showed an augmented response to bladder distension. By contrast, P2X antagonists [2',3'-O-(2,4,6-trinitrophenyl)-ATP and pyridoxal 5-phosphate 6-azophenyl-2',4'-disulfonic acid] and capsaicin attenuated distension-induced discharges in bladder afferents. These data strongly suggest a major sensory role for urothelially released ATP acting via P2X₃ receptors on a subpopulation of pelvic afferent fibers.

Key words: ATP; P2X₃ receptor; pelvic afferents; immunohistochemistry; capsaicin; knock-out; mouse; urinary bladder

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21155670-08$05.00/0

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