P2X receptor channels in chronic pain pathways

Abstract

Chronic pain is a highly prevalent debilitating condition for which treatment options remain limited for many patients. Ionotropic ATP signalling through excitatory and calcium-permeable P2X receptor channels is now rightfully considered as a critical player in pathological pain generation and maintenance; therefore, their selective targeting represents a therapeutic opportunity with promising yet untapped potential. Recent advances in the structural, functional and pharmacological characterization of rodent and human ATP-gated P2X receptor channels have shed brighter light on the role of specific subtypes in the pathophysiology of chronic inflammatory, neuropathic or cancer pain. Here, we will review the contribution of P2X3, P2X4 and P2X7 receptors to chronic pain and discuss the opportunities and challenges associated with the pharmacological manipulation of their function.

Linked articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Figure 1

Schematic cellular distribution of the main P2X receptor subtypes expressed in mammalian peripheral pain pathways. The exact subunit stoichiometry of native heteromeric P2X2/3 receptors in primary sensory neurons remains unknown.

Figure 2

Crystal structure of the trimeric human P2X3 receptor channel showing interactions with the competitive antagonist A‐317491 bound to the orthosteric ATP site. Cartoon (left), space fill (centre) and ball‐and‐stick (right) representations are displayed in two orientations. The dashed lines indicate the position of the lipid bilayer. Coordinates from PDB #5SVR (Mansoor et al., 2016) viewed in JSmol.

Figure 3

Structures of subtype‐selective P2X receptor antagonists. The compounds IP5I and RO‐85 can discriminate between P2X3 homomers and P2X2/3 heteromers. The orally bioavailable compound AF‐219 is currently tested in Phase III clinical trials for hypersensitized C‐fibre afferents and refractory chronic cough.