Spatial and temporal activation of spinal glial cells: Role of gliopathy in central neuropathic pain following spinal cord injury in rats

Abstract

In the spinal cord, neurons and glial cells actively interact and contribute to neurofunction. Surprisingly, both cell types have similar receptors, transporters and ion channels and also produce similar neurotransmitters and cytokines. The neuroanatomical and neurochemical similarities work synergistically to maintain physiological homeostasis in the normal spinal cord. However, in trauma or disease states, spinal glia become activated, dorsal horn neurons become hyperexcitable contributing to sensitized neuronal-glial circuits. The maladaptive spinal circuits directly affect synaptic excitability, including activation of intracellular downstream cascades that result in enhanced evoked and spontaneous activity in dorsal horn neurons with the result that abnormal pain syndromes develop. Recent literature reported that spinal cord injury produces glial activation in the dorsal horn; however, the majority of glial activation studies after SCI have focused on transient and/or acute time points, from a few hours to one month, and peri-lesion sites, a few millimeters rostral and caudal to the lesion site. In addition, thoracic spinal cord injury produces activation of astrocytes and microglia that contributes to dorsal horn neuronal hyperexcitability and central neuropathic pain in above-level, at-level and below-level segments remote from the lesion in the spinal cord. The cellular and molecular events of glial activation are not a simple event, rather it is the consequence of a combination of several neurochemical and neurophysiological changes following SCI. The ionic imbalances, neuroinflammation and alterations of cell cycle proteins after SCI are predominant components for neuroanatomical and neurochemical changes that result in glial activation. More importantly, SCI induced release of glutamate, proinfloammatory cytokines, ATP, reactive oxygen species (ROS) and neurotrophic factors trigger activation of postsynaptic neurons and glial cells via their own receptors and channels that, in turn, contribute to neuronal-neuronal and neuronal-glial interaction as well as microglia-astrocytic interactions. However, a systematic review of temporal and spatial glial activation following SCI has not been done. In this review, we describe time and regional dependence of glial activation and describe activation mechanisms in various SCI models in rats. These data are placed in the broader context of glial activation mechanisms and chronic pain states. Our work in the context of work by others in SCI models demonstrate that dysfunctional glia, a condition called “gliopathy”, are key contributors in the underlying cellular mechanisms contributing to neuropathic pain.

Cell Cycle Activation Contributes to Increased Neuronal Activity in the Posterior Thalamic Nucleus and Associated Chronic Hyperesthesia after Rat Spinal Cord Contusion

“…ED1-positive reactive microglia were rarely seen in uninjured tissue (Fig. 7a), but 5 weeks after SCI, ED1 + /Iba-1 + cells were significantly increased in the injured tissue compared with sham tissue, consistent with other reports [67]. Notably, there was a significant reduction in positively-stained cells in CR8-treated animals ( Fig.…”

Nor-Binaltorphimine Blocks the Adverse Effects of Morphine after Spinal Cord Injury

“…[41][42][43] In the current study, treatment with norBNI decreased signs of pain in the chronic phase of injury. Assessed at the end of the 21 day recovery period, rats treated with the highest dose of norBNI (0.32 lmol) showed significantly higher thresholds than controls (0 lmol norBNI) in tests of thermal and tactile (hindpaw) reactivity.…”

Overexpression of the Astrocyte Glutamate Transporter GLT1 Exacerbates Phrenic Motor Neuron Degeneration, Diaphragm Compromise, and Forelimb Motor Dysfunction following Cervical Contusion Spinal Cord Injury

“…Even though secondary degeneration is relatively protracted following SCI, temporal dynamics of this process vary across cell types. We previously demonstrated that PhMNs are lost mostly during the first day after cervical contusion (Nicaise et al, 2013), suggesting that early GLT1 downregulation we observed is relevant to PhMN protection/loss, while persistent decrease in GLT1 is likely more relevant to other SCI outcomes, such as delayed oligodendrocyte injury and neuronal hyperexcitability (Gwak and Hulsebosch, 2011). Therefore, we chose to test GLT1 overexpression at early time points after injury for PhMN protection.…”

“…After CNS trauma, areas of focal damage are surrounded by an astroglial scar that separates necrotic from spared tissue (Kawano et al, 2012). Transgenic ablation of the proliferating astrocytes that contribute to this process post-SCI leads to increased inflammation, demyelination, lesion volume, and neuronal loss (Faulkner et al, 2004).…”

“…Several studies have shown that GLT1 expression is chronically reduced following thoracic SCI Min et al, 2012). Changes in GLT1 expression appear to be spatiotemporally regulated in a more subtle manner (Xu et al, 2008;Gwak et al, 2012). Rapid GLT1 upregulation has been reported within the first hours post-SCI (Vera-Portocarrero et al, 2002) in surviving astrocytes (Xu et al, 2008).…”