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

Abstract

The P2X(7) 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)-1beta 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-1beta, 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-1beta 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 P2X(7) receptor, via regulation of mature IL-1beta 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.

Physiological and pathological functions of P2X7 receptor in the spinal cord

“…For instance, ATP is the major mediator of pain signaling in the spinal cord [19] and promotes the release of interleukin 1 and other proinflammatory cytokines during injury [20,65].…”

“…Knock-down studies revealed suppression of tactile allodynia after the injury [66]. A role for P2X7R in the development of neuropathic pain has come from studies where alteration in the P2X7 receptor pathway also shows reduction of neuropathic pain [65]. This receptor is also overexpressed in patients with chronic pain and disruption of the receptor leads to impairment in the production of IL-1β, IL-10, and IL-6, evidencing its strong involvement in inflammatory responses [67,65].…”

“…A role for P2X7R in the development of neuropathic pain has come from studies where alteration in the P2X7 receptor pathway also shows reduction of neuropathic pain [65]. This receptor is also overexpressed in patients with chronic pain and disruption of the receptor leads to impairment in the production of IL-1β, IL-10, and IL-6, evidencing its strong involvement in inflammatory responses [67,65]. Importantly, systemic administration of P2X7R antagonists produced a dose-dependent reduction of neuropathic pain [68,69].…”

A genome‐wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain

“…Chessell et al. (2005) reported that P2X7 purinoceptor gene is essential for neuropathic pain. Trang et al.…”

Natural compounds with P2X7 receptor-modulating properties

“…Some of them are associated with different pathologies, including tuberculosis, Crohn's disease or bipolar affective disorders (reviewed by [10]). Genetically engineered mouse models lacking P2X7 expression in distinct tissues showed an attenuation of the release of pro-inflammatory cytokines [11], thereby decreasing the incidence and severity of arthritis [12] and reducing inflammatory and neuropathic pain sensitivity [13]. Thus, the P2X7 has attracted considerable interest as a therapeutic target [7,14].…”