P2X receptor ligands and pain

Abstract

P2X receptors belong to a superfamily of ligand-gated ion channels that conduct the influx of Ca²⁺, 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 ~ 40 – 50% identity in amino acid sequences within the subfamily. Using gene-silencing, pharmacological and electrophysiological approaches, recent studies have revealed roles for P2X₂, P2X₃, P2X₄ and P2X₇ receptors in nociceptive signalling. Homomeric P2X₃ 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 P2X₃ antagonist, provided a pharmacological tool to determine the site and mode of action of P2X₃-containing receptors in different pain behaviours, including neuropathic, inflammatory and visceral pain. Other P2X receptors (P2X₄ and P2X₇) that are predominantly expressed in microglia, macrophages and cells of immune origin can trigger the release of cytokines, such as IL-1-β and TNF-α. Genetic disruption of P2X₄ and P2X₇ 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 P2X₃, P2X₄ and P2X₇ receptors, and the identification of small molecule ligands for the potential treatment of neuropathic and inflammatory pain.

Keywords: A-317491,:

• allodynia
• hyperalgesia
• inflammation
• inflammatory pain
• neuropathic pain
• P2X₂
• P2X₃
• P2X₄
• P2X₇
• purinergic receptor