Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

• Brain glial activation is observed in patients suffering from chronic low back pain.
• Microglia maintain a dynamic relationship with neurons.
• Astrocytic connexin hemichannels play a role in injury-induced pain hypersensitivity.
• Neuron–glial signaling in the spinal cord can be triggered by descending input.
• Enhanced glial activity also offers neuroprotection as suggested by human studies.

Recent studies continue to support the proposition that non-neuronal components of the nervous system, mainly glial cells and associated chemical mediators, contribute to the development of neuronal hyperexcitability that underlies persistent pain conditions. In the event of peripheral injury, enhanced or abnormal nerve input is likely the most efficient way to activate simultaneously central neurons and glia. Injury induces phenotypic changes in glia and triggers signaling cascades that engage reciprocal interactions between presynaptic terminals, postsynaptic neurons, microglia and astrocytes. While some responses to peripheral injury may help the nervous system to adapt positively to counter the disastrous effect of injury, the net effect often leads to long-lasting sensitization of pain transmission pathways and chronic pain.