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¹ Roche Palo Alto, Palo Alto, CA 94304, USA
² Autonomic Neuroscience Institute, Royal Free and University College Medical School, London NW3 2PF, UK
³ Department of Biomedical Science, University of Sheffield, UK
⁴ Neurorestoration Group, CARD, Kings College London SE1 9RT, UK

Extracellular ATP plays a role in nociceptive signalling and sensory regulation of visceral function through ionotropic receptors variably composed of P2X₂ and P2X₃ subunits. P2X₂ and P2X₃ subunits can form homomultimeric P2X₂, homomultimeric P2X₃, or heteromultimeric P2X_2/3 receptors. However, the relative contribution of these receptor subtypes to afferent functions of ATP in vivo is poorly understood. Here we describe null mutant mice lacking the P2X₂ receptor subunit (P2X₂^–/–) and double mutant mice lacking both P2X₂ and P2X₃ subunits (P2X₂/P2X₃^Dbl–/–), and compare these with previously characterized P2X₃^–/– mice. In patch-clamp studies, nodose, coeliac and superior cervical ganglia (SCG) neurones from wild-type mice responded to ATP with sustained inward currents, while dorsal root ganglia (DRG) neurones gave predominantly transient currents. Sensory neurones from P2X₂^–/– mice responded to ATP with only transient inward currents, while sympathetic neurones had barely detectable responses. Neurones from P2X₂/P2X₃^Dbl–/– mice had minimal to no response to ATP. These data indicate that P2X receptors on sensory and sympathetic ganglion neurones involve almost exclusively P2X₂ and P2X₃ subunits. P2X₂^–/– and P2X₂/P2X₃^Dbl–/– mice had reduced pain-related behaviours in response to intraplantar injection of formalin. Significantly, P2X₃^–/–, P2X₂^–/–, and P2X₂/P2X₃^Dbl–/– mice had reduced urinary bladder reflexes and decreased pelvic afferent nerve activity in response to bladder distension. No deficits in a wide variety of CNS behavioural tests were observed in P2X₂^–/– mice. Taken together, these data extend our findings for P2X₃^–/– mice, and reveal an important contribution of heteromeric P2X_2/3 receptors to nociceptive responses and mechanosensory transduction within the urinary bladder.

(Received 14 April 2005; accepted after revision 15 June 2005; first published online 16 June 2005)
Corresponding author D. A. Cockayne: Roche Palo Alto, 3431 Hillview Avenue, Palo Alto, CA 94304, USA. Email: debra.cockayne{at}roche.com

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