P2X receptors belong to a superfamily of
ligand-gated ion channels that conduct the influx of Ca(2+), Na(+) and K(+)
cations following activation by extracellular
nucleotides such as
ATP. Molecular cloning studies have identified seven subunits, namely P2X(1-7), that share approximately 40 - 50% identity in amino acid sequences within the subfamily. Using gene-silencing, pharmacological and electrophysiological approaches, recent studies have revealed roles for P2X(2), P2X(3), P2X(4) and P2X(7) receptors in nociceptive signalling. Homomeric P2X(3) and heteromeric P2X(2/3) receptors are highly localised in the peripheral sensory afferent neurons that conduct nociceptive sensory information to the spinal chord and brain. The discovery of
A-317491, a selective and potent non-
nucleotide P2X(3) antagonist, provided a pharmacological tool to determine the site and mode of action of P2X(3)-containing receptors in different
pain behaviours, including neuropathic, inflammatory and
visceral pain. Other P2X receptors (P2X(4) and P2X(7)) that are predominantly expressed in microglia, macrophages and cells of immune origin can trigger the release of
cytokines, such as IL-1-beta and
TNF-alpha. Genetic disruption of P2X(4) and P2X(7) signalling has been demonstrated to reduce inflammatory and
neuropathic pain, suggesting that these two receptors might serve as integrators of
neuroinflammation and
pain. This article provides an overview of recent scientific literature and patents focusing on P2X(3), P2X(4) and P2X(7) receptors, and the identification of small molecule
ligands for the potential treatment of neuropathic and inflammatory
pain.