Modulating the delicate glial–neuronal interactions in neuropathic pain: Promises and potential caveats

Abstract

During neuropathic pain, glial cells (mainly astrocytes and microglia) become activated and initiate a series of signaling cascades that modulate pain processing at both spinal and supraspinal levels. It has been generally accepted that glial cell activation contributes to neuropathic pain because glia release proinflammatory cytokines, chemokines, and factors such as calcitonin gene-related peptide, substance P, and glutamate, which are known to facilitate pain signaling. However, recent research has shown that activation of glia also leads to some beneficial outcomes. Glia release anti-inflammatory factors that protect against neurotoxicity and restore normal pain. Accordingly, use of glial inhibitors might compromise the protective functions of glia in addition to suppressing their detrimental effects. With a better understanding of how different conditions affect glial cell activation, we may be able to promote the protective function of glia and pave the way for future development of novel, safe, and effective treatments of neuropathic pain.

Activity-triggered tetrapartite neuron–glial interactions following peripheral injury

“…Neuroprotection is in fact a major function of glia, although the net effect of increased glial activity after injury is often pronociceptive [3,79,80]. The TSPO agonist has been shown to attenuate persistent pain in animal models [10,11].…”

The Cerebrospinal Fluid in Severe Pain Conditions : Clinical, Pharmacological and Proteomic Aspects

“…Hence, our results are in agreement with several other recent lines of evidence, suggesting a role for the RAS in the pathophysiology of neuropathic pain. Given that angiotensinogen is synthesized by astrocytes, one might speculate that our findings perhaps indicate glial activation in human neuropathic pain [157,236]. Although many animal studies have shown glial activation in neuropathic pain models, direct evidence for glial involvement in humans has hitherto been almost non-existent [236].…”

“…CNS microglia are thought to be important initiators of neuropathic pain, whereas astrocytes have a role in the maintainance of neuropathic pain [76]. However, there is a knowledge gap between animal models and clinical pain medicine: whereas glial changes are evident in animal models of neuropathic pain, evidence for such changes in humans are almost non-existent, and glial cells (at least astrocytes) from mice and monkeys are quite different from humans [236].…”

Gene therapy for neuropathic pain induced by spared nerve injury with naked plasmid encoding hepatocyte growth factor

“…1 Previous studies reported that blockade of the activation of spinal microglia and astrocytes attenuated pain hypersensitivity. Peripheral nerve injury leads to activation of microglia and astrocytes, and this activation can contribute to the amplification of pain via the production and release of proinflammatory cytokines and neuroexcitatory substances.…”