ABSTRACT
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 P2X2/3 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 P2X2/3 receptors to nociceptive responses and mechanosensory transduction within the urinary bladder.
Subject(s)
Adenosine Triphosphate/metabolism , Mechanotransduction, Cellular , Neurons, Afferent/metabolism , Pain/metabolism , Receptors, Purinergic P2/metabolism , Urinary Bladder/physiopathology , Animals , Mice , Mice, Knockout , Muscle Contraction , Protein Subunits , Receptors, Purinergic P2/chemistry , Receptors, Purinergic P2/genetics , Receptors, Purinergic P2X2 , Receptors, Purinergic P2X3 , Reflex , Structure-Activity Relationship , Urinary Bladder/innervationABSTRACT
Many decades have passed since the pain-producing properties of ATP were demonstrated in both animals and humans. However, the more recent discovery of a family of ion channels for which ATP is a ligand and which are expressed by nociceptive neurons, has led to a resurgence of interest into the physiological and pathophysiological actions of ATP. This article considers the extent to which available evidence supports the notion that ATP receptors might be important novel analgesic targets. The hypothesis that ATP is a pain mediator is considered in terms of: the distribution of ATP receptors (specifically the P2X ion channel family); whether ATP release occurs under appropriate conditions; the evidence that ATP is capable of initiating pain in humans and pain-related behaviour in animals; and, lastly, the analgesic effects of pharmacological or molecular block of ATP receptors.