A growing body of evidence indicates that extracellular nucleotides released or leaked from non-excitable cells as well as neurons play important roles in the regulation of neuronal and glial functions in the whole body through ATP receptors. ATP receptors (ionotropic P2X and metabotropic P2Y receptors) are the most abundant receptor families in living organisms. In the central nervous system, these receptors participate in synaptic transmission and in intercellular communications between neurons and glia. Glia cells are classified into astrocytes, oligodendrocytes and microglia. There are many reports on the role of ATP receptors (P2X4, P2X7, P2Y6 and P2Y12 receptors) expressed in spinal microglia. We have reported that several molecules presumably activate microglia in neuropathic pain after peripheral nerve injury. P2X4 receptors expressed in microglia in particular play a critical role in neuropathic pain signaling. The expression and activity of P2X4 receptors are up-regulated and enhanced predominantly in activated microglia in the spinal cord where damaged sensory fibers project. These findings provide novel targets for developing new medicines to treat neuropathic pain.