Reactive Astrocytes: Critical Players in the Development of Chronic Pain

James Tang, Mercedes Bair, Giannina Descalzi, James Tang, Mercedes Bair, Giannina Descalzi

Abstract

Chronic pain is associated with long term plasticity of nociceptive pathways in the central nervous system. Astrocytes can profoundly affect synaptic function and increasing evidence has highlighted how altered astrocyte activity may contribute to the pathogenesis of chronic pain. In response to injury, astrocytes undergo a shift in form and function known as reactive astrogliosis, which affects their release of cytokines and gliotransmitters. These neuromodulatory substances have been implicated in driving the persistent changes in central nociceptive activity. Astrocytes also release lactate which neurons can use to produce energy during synaptic plasticity. Furthermore, recent research has provided insight into lactate's emerging role as a signaling molecule in the central nervous system, which may be involved in directly modulating neuronal and astrocytic activity. In this review, we present evidence for the involvement of astrocyte-derived tumor necrosis factor alpha in pain-associated plasticity, in addition to research suggesting the potential involvement of gliotransmitters D-serine and adenosine-5'-triphosphate. We also discuss work implicating astrocyte-neuron metabolic coupling, and the possible role of lactate, which has been sparsely studied in the context of chronic pain, in supporting pathological changes in central nociceptive activity.

Keywords: TNFα; astrocytes; chronic pain; cytokine; gliotransmission; lactate; plasticity.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Tang, Bair and Descalzi.

Figures

Figure 1
Figure 1
Potential astrocyte-neuron signaling pathways in modulating pain-related synaptic transmission. (1) TNFα acts on neuronal TNFR1 resulting in rapid trafficking of GluR2-lacking AMPA receptors to the postsynaptic membrane and internalization of postsynaptic GABAA receptors. (2) TNFα increases presynaptic glutamate release, potentially by activating or increasing the expression of transient receptor potential subtype V1. (3) TNFα acts on astrocytic TNFR1, inducing phosphorylation of JNK. JNK phosphorylates c-Jun, which dimerizes with c-Fos to form the AP-1 transcription factor, leading to transcription of target genes such as MCP-1 and MMP-2. (4) MCP-1 is released from astrocytes where it can act on neurons via CCR2, modulating their excitability. (5) ATP released from astrocytes may act on pre-synaptic neuronal P2X3 and P2X7 receptors, stimulating glutamate release.
Figure 2
Figure 2
Potential mechanisms through which astrocyte-neuronal metabolic coupling and lactate release can mediate pain-related neuronal activity. (1) Lactate taken up by neurons via MCT2 is converted to pyruvate, where it can be used to generate ATP through oxidative phosphorylation. (2) Neurons express HCAR1, a Gi-protein coupled receptor which inhibits adenylyl cyclase and reduces intracellular cAMP. Neurons also appear to express an unidentified lactate receptor which activates adenylyl cyclase and increases cAMP. (3) Similarly, astrocytes have been found to express HCAR1, however recent findings also suggest the presence of a lactate receptor which exerts opposite effects and activates rather than inhibits adenylyl cyclase. (4) Lactate binding to HCAR1 was recently associated with a non-Gi-protein mechanism, acting through β-arrestin2-MAPK-signaling. The β-arrestin2-MAPK pathway has been associated with induction of astrocyte proliferation. (5) Glutamate released into the synaptic cleft is taken up by astrocytes via GLT-1 and GLAST. Astrocytic GS converts glutamate to glutamine, which is exported and taken up by neurons. Altered GLT-1/GLAST expression may affect synaptic transmission through dysregulation of extracellular glutamate concentrations.

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