Contributions of P2X3 homomeric and heteromeric channels to acute and chronic pain.

ATP acts as a fast neurotransmitter by activating a family of ligand-gated ion channels, the P2X receptors. Functional homomeric (P2X(3)) and heteromeric (P2X(2/3)) receptors are highly localised on primary sensory afferent neurons that transmit nociceptive sensory information. Activation of these P2X(3)containing channels may provide a specific mechanism whereby ATP, released via synaptic transmission or by cellular injury, elicits pain. The physiological relevance of the pro-nociceptive actions of ATP is supported by data demonstrating that the exogenous peripheral or spinal administration of ATP and other P2X receptor agonists elicits nociceptive behaviour and increases sensitivity to noxious stimuli in both humans and laboratory animals. The nociceptive effects of P2X receptor agonists are also enhanced in the presence of inflammatory mediators. Both permanent (P2X(3) gene knockout) and transient (P2X(3) antisense) receptor gene disruption studies in laboratory rodents have provided hypoalgesic phenotypes, further supporting a role for P2X(3) subunits in contributing to the expression of pain. More recently, the acute systemic administration of a highly selective non-nucleotide P2X(3) antagonist, A317491, has been shown to fully block specific types of chronic inflammatory and neuropathic pain in animal models in the absence of cardiovascular and CNS side effects associated with other analgesic compounds. Therefore, both genetic and pharmacological approaches have provided converging evidence that activation of P2X(3)-containing channels is an important mediator of persistent nociceptive signalling. The available data also indicate potential discrete roles for homomeric P2X(3) and heteromeric P2X(2/3) receptor activation in acute and chronic pain.