P2X4R and P2X7R in neuropathic pain

Neuropathic pain is often a consequence of nerve injury or of diseases such as diabetes, infection, autoimmune disease, or cancer. Neuropathic pain can be agonizing, can persist over long periods, and, unfortunately, is often resistant to known painkillers. There is a rapidly growing body of evidence indicating that signaling by extracellular nucleotides through purinergic P2 receptors [ionotropic P2X receptors (P2XRs) and metabotropic P2Y receptors (P2YRs)] play crucial roles in neuropathic pain. Following peripheral nerve injury, the expression of purinergic receptors (e.g., P2X4R) is markedly upregulated specifically in microglia, a type of glial cells known as resident macrophages in the central nervous system. Activation of P2X4R and P2X7R in microglia causes release of diffusible factors (such as brain-derived neurotrophic factor, interleukin-1β, interleukin-6, and tumor necrosis factor-α) involved in nerve-injury-induced pain behaviors and hyperexcitability of dorsal horn neurons. Suppression of the function or expression of these purinergic receptors strongly suppresses neuropathic pain. Recent advances further our understanding of mechanisms by which microglial purinergic receptors contribute to the pathogenesis of neuropathic pain.