Pharmacological characterization of P2X3 homomeric and heteromeric channels in nociceptive signaling and behavior

ATP acts as a fast neurotransmitter by activating a family of ligand-gated ion channels, the P2X receptors. The P2X(3) receptor subunit, in both homomeric and heteromeric (P2X(2/3)) forms, is highly localized on primary sensory afferent neurons that function as nociceptors. Activation of these P2X(3) containing channels may provide a specific mechanism whereby ATP, released via synaptic transmission or by cellular injury, elicits nociceptive sensations. This hypothesis is supported by recent data demonstrating that the exogenous peripheral or spinal administration of ATP and other P2X receptor agonists elicits nociceptive behaviors and increases sensitivity to noxious stimuli in both humans and laboratory animals. The nociceptive effects of ATP and other P2X receptor agonists are also enhanced in the presence of other inflammatory mediators. P2X receptor antagonists can attenuate the nociceptive actions of exogenously administered P2X receptor agonists and other exogenously administered algogenic agents. However, pharmacological characterization of these effects has been complicated by the general lack of highly selective ligands for the family of P2X receptor subunits and the ability of these receptors to farm functional heteromultimeric receptors. Recent data describing an aberrant nociceptive phenotype of P2X(3) receptor gene-disrupted mice have provided additional insight into the role of P2X(3) receptors in some types of pain. An overview of the pharmacology of P2X(3) containing channels and the experimental data indicating that activation of P2X(3) receptors contribute to the initiation and maintenance of persistent pain is presented in this review. Drug Dev. Res. 52:220-231, 2001. (C) 2001 Wiley-Liss, Inc.