Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice

Debra A. Cockayne (), Sara G. Hamilton, Quan-Ming Zhu, Philip M. Dunn, Yu Zhong, Sanja Novakovic, Annika B. Malmberg, Gary Cain, Amy Berson, Laura Kassotakis, Linda Hedley, Wilhelm G. Lachnit, Geoffrey Burnstock, Stephen B. McMahon and Anthony P. D. W. Ford
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Debra A. Cockayne: The Neurobiology Unit, Roche Bioscience
Sara G. Hamilton: Centre for Neuroscience Research, Kings College London
Quan-Ming Zhu: The Neurobiology Unit, Roche Bioscience
Philip M. Dunn: Autonomic Neuroscience Institute, Royal Free and University College Medical School
Yu Zhong: Autonomic Neuroscience Institute, Royal Free and University College Medical School
Sanja Novakovic: The Neurobiology Unit, Roche Bioscience
Annika B. Malmberg: The Neurobiology Unit, Roche Bioscience
Gary Cain: The Neurobiology Unit, Roche Bioscience
Amy Berson: The Neurobiology Unit, Roche Bioscience
Laura Kassotakis: The Neurobiology Unit, Roche Bioscience
Linda Hedley: The Neurobiology Unit, Roche Bioscience
Wilhelm G. Lachnit: The Neurobiology Unit, Roche Bioscience
Geoffrey Burnstock: Autonomic Neuroscience Institute, Royal Free and University College Medical School
Stephen B. McMahon: Centre for Neuroscience Research, Kings College London
Anthony P. D. W. Ford: The Neurobiology Unit, Roche Bioscience

Nature, 2000, vol. 407, issue 6807, 1011-1015

Abstract: Abstract Extracellular ATP is implicated in numerous sensory processes ranging from the response to pain to the regulation of motility in visceral organs1. The ATP receptor P2X3 is selectively expressed on small diameter sensory neurons2,3,4, supporting this hypothesis. Here we show that mice deficient in P2X3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X3-null mice have reduced pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X3-null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localize P2X3 to nerve fibres innervating the urinary bladder of wild-type mice, and show that loss of P2X3 does not alter sensory neuron innervation density. Thus, P2X3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder.

Date: 2000
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DOI: 10.1038/35039519

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