Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-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 . The ATP receptor P2X 3 is selectively expressed on small diameter sensory neurons 2 , 3 , 4 , supporting this hypothesis. Here we show that mice deficient in P2X 3 lose the rapidly desensitizing ATP-induced currents in dorsal root ganglion neurons. P2X 3 deficiency also causes a reduction in the sustained ATP-induced currents in nodose ganglion neurons. P2X 3 -null mice have reduced pain-related behaviour in response to injection of ATP and formalin. Significantly, P2X 3 -null mice exhibit a marked urinary bladder hyporeflexia, characterized by decreased voiding frequency and increased bladder capacity, but normal bladder pressures. Immunohistochemical studies localize P2X 3 to nerve fibres innervating the urinary bladder of wild-type mice, and show that loss of P2X 3 does not alter sensory neuron innervation density. Thus, P2X 3 is critical for peripheral pain responses and afferent pathways controlling urinary bladder volume reflexes. Antagonists to P2X 3 may therefore have therapeutic potential in the treatment of disorders of urine storage and voiding such as overactive bladder.