Neuronal-Glial Interactions Maintain Chronic Neuropathic Pain after Spinal Cord Injury

Figure 2

Intercellular and intracellular mechanisms driving persistent neuronal hyperactivity following SCI. After SCI, activated primary afferent fibers release pain-mediating substances on both postsynaptic neurons and activated glial cells. Elevation of calcium ion concentrations in neurons and activated glial cells triggers similar intracellular downstream events in both neurons and glial cells, that is, activation (phosphorylation) of p38-MAPK and ERK, followed by activation of posttranscriptional and posttranslational processes that result in altered protein and ion channel expression. In neurons, elevated calcium ion concentrations also trigger activation of calcium-dependent (direct) pathways and calcium-independent (indirect) PLA₂ pathways, followed by increased AA, ROS, and PG synthesis. These effects contribute to the development of persistent neuronal hyperactivity. Activated glial cells release gliotransmitters to the extracellular space, thereby activating receptors and/or ion channels in the neuronal membrane. Subsequently, gliotransmission activates neural membrane receptors and/or ion channels, thereby triggering a massive influx of cations (Na⁺ and Ca²⁺) into the intracellular compartments of neurons. This positive feedforward cycle maintains persistent neuronal hyperactivity, which plays a key role in the development of neuropathic pain after SCI. p38-MAPK: p38 mitogen-activated protein kinases; ERK: extracellular signal-regulated kinases; 5-HTRs: 5-serotonin receptor; AA: arachidonic acid; APs: action potentials; EAAs: excitatory amino acids; ILRs: interleukin receptors; NKR: neurokinin receptor; PGs: prostaglandins; PLA₂: phospholipase A₂; ROS/RNS: reactive oxygen/nitrogen species; TLRs: toll-like receptors; TRPs: transient receptor potential channels.