Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X(3)-deficient mice

Extracellular ATP is implicated in numerous sensory processes ranging from the response to pain to the regulation of motility in visceral organs(1). T he ATP receptor P2X(3) is selectively expressed on small diameter sensory n eurons(2-4), supporting this hypothesis. Here we show that mice deficient i n P2X(3) lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X(3) deficiency also causes a reduction in the sustain ed ATP-induced currents in nodose ganglion neurons. P2X(3)-null mice have r educed pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X(3)-null mice exhibit a marked urinary bladder hyporefle xia, characterized by decreased voiding frequency and increased bladder cap acity, but normal bladder pressures. Immunohistochemical studies localize P 2X(3) to nerve fibres innervating the urinary bladder of wild-type mice, an d show that loss of P2X(3) does not alter sensory neuron innervation densit y. Thus, P2X(3) is critical for peripheral pain responses and afferent path ways controlling urinary bladder volume reflexes. Antagonists to P2X(3) may therefore have therapeutic potential in the treatment of disorders of urin e storage and voiding such as overactive bladder.