Fig. 2

Schematic illustration of P2X receptors involvement in nociceptive transmission and modulation in central pain syndrome. Adenosine triphosphate is an important soluble mediator that is involved in cross-talk between sensory neuron synapses within ascending nociceptive transmission pathways. P2X receptors are expressed in the presynaptic membrane, postsynaptic density, astrocytes, and microglia. In the central pain state, abnormal neuronal excitability and enhanced glutamate/ATP release activate postsynaptic neurons, microglia, and astrocytes, thus contributing to central sensitization and the release of inflammatory mediators and neurotrophins. Currently available evidence strongly suggests a key modulatory role of P2X receptors in central sensitization. Primary nociceptive inputs promote glutamate and ATP co-release and synergistically cause non-selective permeability to Ca²⁺, Na⁺, and K⁺ ions via P2X receptors, leading to the postsynaptic activation of NMDA or AMPA receptors and further contributing astrocytic glutamate and ATP co-release into the extracellular milieu. Intracellular astrocytic Ca²⁺ signals may spread within astrocytes, leading to similar effects at other synapses. Local brain tissue damage resulted ATP release and inflammation can also activate extrasynaptic P2X receptors on microglia. P2X receptors expressed on astrocytes and microglia induces a local inflammatory response with release of cytokines. P2X7 has many consequences in pain, for its role in the inflammasome activation and maturation of IL-1β, one of the most powerful mediators of acute inflammatory response. P2X4 was reported to induce release of BDNF, acting on TrkB receptor which modulates inhibitory neurons, contributing to exacerbation of painful signal transmission pathways in brain centers. Both synaptic and glial release of glutamate and the co-release of neuronal, astrocytic and microglial ATP contribute to synaptic transmission via P2X receptors