Pharmacological characterization of P2X(3) 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 homom eric and heteromeric (P2X(2/3)) forms, is highly localized on primary senso ry afferent neurons that function as nociceptors. Activation of these P2X(3 ) containing channels may provide a specific mechanism whereby ATP, release d via synaptic transmission or by cellular injury, elicits nociceptive sens ations. 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 noxiou s stimuli in both humans and laboratory animals. The nociceptive effects of ATP and other P2X receptor agonists are also enhanced in the presence of o ther inflammatory mediators. P2X receptor antagonists can attenuate the noc iceptive actions of exogenously administered P2X receptor agonists and othe r exogenously administered algogenic agents. However, pharmacological chara cterization of these effects has been complicated by the general lack of hi ghly selective ligands for the family of P2X receptor subunits and the abil ity of these receptors to farm functional heteromultimeric receptors. Recen t data describing an aberrant nociceptive phenotype of P2X(3) receptor gene -disrupted mice have provided additional insight into the role of P2X(3) re ceptors in some types of pain. An overview of the pharmacology of P2X(3) co ntaining channels and the experimental data indicating that activation of P 2X(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.