P2X4 receptor, the first identified P2X receptor, is widely expressed in peripheral nervous system and CNS.157 P2X4 receptors are one of the most abundantly expressed functional purinergic receptors found on glial cells and most neurons17,158 and are upregulated on activated microglia after brain and spinal cord injuries.159 Similar to P2X7R, P2X4R facilitate ion efflux through cell membrane and induces activation of inflammasomes.137 Supporting evidences indicate that P2X4 receptors physically couple with GABAA receptors as well as with the P2X2 receptors and this cross talk may play a role in regulating synaptic signaling and plasticity of neurons.160 Alcohol abuse is known to enhance neuroinflammation through P2X4Rs activation161 and there are suggestions of implication of P2X4Rs in tolerance to morphine and hyperalgesia induction by morphine.161,162 P2X4 receptors are upregulated in TBI6, in acute experimental encephalomyelitis (EAE) rodent model of multiple sclerosis17 and following hypoxia and ischemia events.163 In neurons, P2X4R has shown to stimulate activation of the inflammasome caspase-1 resulting in cytokines IL-18 and IL-β release, and in P2X4R knockout mice, impaired inflammasome signaling was reported to couple to the reduction of
