Cockayne D A, Hamilton S G, Zhu Q M, Dunn P M, Zhong Y, Novakovic S, Malmberg A B, Cain G, Berson A, Kassotakis L, Hedley L, Lachnit W G, Burnstock G, McMahon S B, Ford A P
The Neurobiology Unit, Roche Bioscience, Palo Alto, California 94304, USA.
Nature. 2000 Oct 26;407(6807):1011-5. doi: 10.1038/35039519.
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.
细胞外ATP参与了从疼痛反应到内脏器官运动调节等众多感觉过程。ATP受体P2X3在小直径感觉神经元上选择性表达，支持了这一假说。在此我们表明，P2X3基因缺失的小鼠背根神经节神经元中失去了ATP诱导的快速脱敏电流。P2X3基因缺失还导致结状神经节神经元中ATP诱导的持续电流减少。P2X3基因敲除小鼠对ATP和福尔马林注射的疼痛相关行为有所减少。重要的是，P2X3基因敲除小鼠表现出明显的膀胱反射减退，其特征为排尿频率降低和膀胱容量增加，但膀胱压力正常。免疫组织化学研究将P2X3定位到支配野生型小鼠膀胱的神经纤维上，并表明P2X3的缺失不会改变感觉神经元的神经支配密度。因此，P2X3对于外周疼痛反应和控制膀胱容量反射的传入通路至关重要。因此P2X3拮抗剂在治疗诸如膀胱过度活动症等尿液储存和排尿障碍方面可能具有治疗潜力。
