P2X7 purinergic receptors have been implicated in chronic neuropathic and neuroinflammatory pain as well as in depression. These receptors are predominantly found in the central nervous system on microglial cells and on glutamatergic nerve terminals. Here, we develop hypotheses concerning mechanisms by which transient high-frequency impulse firing in glutamatergic terminals, such as occurs in nociceptor terminals accompanying neuropathic/neuroinflammatory pain, can lead to long-lasting changes in neural network function that is mediated by surrounding glial cells. The hypothesis consists of two parts. In the first, glutamate released by low-frequency (2Hz) terminal action potentials is insufficient to generate postsynaptic action potentials, but these are generated by brief high-frequency input bursts. Glutamate released by these bursts is partly removed by transporters on the enveloping astrocyte processes and also excites AMPA receptors on these processes, which then release ATP. This ATP is partly metabolised to adenosine, which acts on presynaptic A1 receptors to inhibit glutamate release. The remaining ATP acts on the presynaptic P2X7 receptors to facilitate glutamate release by both the high-frequency burst of action potentials as well as by a continuous low-frequency (2Hz) action potential firing that occurs in the absence of a neuropathic/neuroinflammatory insult. The positive feedback of terminal glutamate release, triggering astrocyte ATP release and leading to further glutamate release through activation of P2X7 receptors, is then sufficient to allow the normal low-frequency (2Hz) action potentials to now elicit postsynaptic action potentials after the insult is removed. In the second part of this model, the high concentration of ATP derived from astrocytes at the terminal attracts microglia by chemotaxis. The P2X7 receptors on these microglia are then engaged, resulting in microglia secreting the cytokine TNFalpha. This acts on postsynaptic TNF-R1 receptors to increase the number of AMPA receptors there, thus enhancing the efficacy of synaptic transmission. The TNFalpha also acts on presynaptic TNF-R1 to increase the amount of glutamate released by each nerve terminal impulse. Experimental tests can be made of this hypothesis that P2X7 receptors on the presynaptic terminal and those on the microglia synergistically act to ensure feedback pathways that reset to a high level the efficacy of synaptic transmission, thus ensuring chronic neuropathic/neuroinflammatory pain even when the initial insult has subsided.