Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain

TLDR

The P2X7 purinoceptor is a ligand‑gated cation channel expressed mainly by immune cells that uniquely releases the inflammatory cytokine IL‑1β upon activation. The study hypothesizes that P2X7‑mediated IL‑1β production drives both inflammatory and neuropathic pain, suggesting that its blockade could yield broad‑spectrum analgesia. Mice lacking P2X7 exhibit complete loss of inflammatory and neuropathic hypersensitivity while preserving normal nociception, with selective reductions in IL‑1β, IL‑10, IL‑6, and MCP‑1, and the receptor is upregulated in human dorsal root ganglia and injured nerves from chronic pain patients.

Abstract

The P2X7 purinoceptor is a ligand-gated cation channel, expressed predominantly by cells of immune origin, with a unique phenotype which includes release of biologically active inflammatory cytokine, interleukin (IL)-1β following activation, and unique ion channel biophysics observed only in this receptor family. Here we demonstrate that in mice lacking this receptor, inflammatory (in an adjuvant-induced model) and neuropathic (in a partial nerve ligation model) hypersensitivity is completely absent to both mechanical and thermal stimuli, whilst normal nociceptive processing is preserved. The knockout animals were unimpaired in their ability to produce mRNA for pro-IL-1β, and cytometric analysis of paw and systemic cytokines from knockout and wild-type animals following adjuvant insult suggests a selective effect of the gene deletion on release of IL-1β and IL-10, with systemic reductions in adjuvant-induced increases in IL-6 and MCP-1. In addition, we show that this receptor is upregulated in human dorsal root ganglia and injured nerves obtained from chronic neuropathic pain patients. We hypothesise that the P2X7 receptor, via regulation of mature IL-1β production, plays a common upstream transductional role in the development of pain of neuropathic and inflammatory origin. Drugs which block this target may have the potential to deliver broad-spectrum analgesia.