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. The ATP receptor P2X3 is selectively expressed on small diameter sensory neurons, 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.
Cockayne
D A
DA
The Neurobiology Unit, Roche Bioscience, Palo Alto, California 94304, USA. debra.cockayne@roche.com
Hamilton
S G
SG
Zhu
Q M
QM
Dunn
P M
PM
Zhong
Y
Y
Novakovic
S
S
Malmberg
A B
AB
Cain
G
G
Berson
A
A
Kassotakis
L
L
Hedley
L
L
Lachnit
W G
WG
Burnstock
G
G
McMahon
S B
SB
Ford
A P
AP
D000255:Adenosine Triphosphate / Q000502:physiology*; D000818:Animals; D018390:Gene Targeting; D051379:Mice; D009474:Neurons / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology; D009619:Nociceptors / Q000502:physiology*; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058477:Receptors, Purinergic P2X3; D012021:Reflex, Abnormal; D001743:Urinary Bladder / Q000294:innervation / Q000502:physiology*; D014563:Urodynamics
C546409:P2rx3 protein, mouse; D018048:Receptors, Purinergic P2; D058477:Receptors, Purinergic P2X3; D000255:Adenosine Triphosphate