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

Abstract

The hyperactive state of sensory neurons in the spinal cord enhances pain transmission. Spinal glial cells have also been implicated in enhanced excitability of spinal dorsal horn neurons, resulting in pain amplification and distortions. Traumatic injuries of the neural system such as spinal cord injury (SCI) induce neuronal hyperactivity and glial activation, causing maladaptive synaptic plasticity in the spinal cord. Recent studies demonstrate that SCI causes persistent glial activation with concomitant neuronal hyperactivity, thus providing the substrate for central neuropathic pain. Hyperactive sensory neurons and activated glial cells increase intracellular and extracellular glutamate, neuropeptides, adenosine triphosphates, proinflammatory cytokines, and reactive oxygen species concentrations, all of which enhance pain transmission. In addition, hyperactive sensory neurons and glial cells overexpress receptors and ion channels that maintain this enhanced pain transmission. Therefore, post-SCI neuronal-glial interactions create maladaptive synaptic circuits and activate intracellular signaling events that permanently contribute to enhanced neuropathic pain. In this review, we describe how hyperactivity of sensory neurons contributes to the maintenance of chronic neuropathic pain via neuronal-glial interactions following SCI.

Figure 1

Neuropathic pain behavior and neuronal hyperactivity following SCI. ((a), left) Compared to the sham group (closed circle), the SCI group (open circle) shows complete loss of locomotion at early phase (days 1 to 4) following contusive spinal cord injury (SCI) at the thoracic segment T10. However, three weeks after SCI, animals gradually recover locomotion, showing BBB scores over 7, and are enable to position and withdrawal responses. The BBB scores are averaged by left and right sides of the hindlimbs. ((a), right) Pain behaviors were measured by paw withdrawal thresholds (PTWs), which are determined by quantitative assessment of withdrawal behaviors ([33]). On three weeks after SCI, pain behaviors develop (decrease of PWTs scores) and maintained. (b) On four to five weeks after SCI, lumbar spinal wide dynamic range (WDR) dorsal horn neurons (neurons that respond to all three stimuli: brush, pressure, and pinch in their peripheral receptive field) display significantly increased evoked activity in response to all three stimuli (10 seconds each) compared to the sham group (modified from Gwak et al. [28]). Br: brush, Pr: pressure, and Pi: pinch stimulation. ^∗p < 0.05 versus the sham group.

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.

Figure 3

Attenuation of neuronal hyperactivity by spinal treatment with PPF following SCI in rats. (a) Typical spike activity during 10 sec (scale bar) of stimulation in the peripheral field during single neuron recordings from sham (top), SCI + vehicle (middle), and SCI + 10 mM PPF- (bottom) treated rats. (b) After SCI, lumbar spinal wide dynamic range (WDR) dorsal horn neurons displayed significantly increased evoked activity in response to peripheral stimuli (10 seconds each) in the SCI-vehicle group compared to the sham group. Two hours after spinal treatment with 10 mM PPF, this activity was significantly attenuated. In contrast, 1 mM PPF had no effect compared to the vehicle treatment (modified from Gwak et al. [4]). ^∗p < 0.05 versus the SCI + vehicle group.