Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jul 9;16(1):140.
doi: 10.1186/s12974-019-1524-2.

An Update on Reactive Astrocytes in Chronic Pain

Affiliations
Free PMC article
Review

An Update on Reactive Astrocytes in Chronic Pain

Ting Li et al. J Neuroinflammation. .
Free PMC article

Abstract

Chronic pain is a critical clinical problem with an increasing prevalence. However, there are limited effective prevention measures and treatments for chronic pain. Astrocytes are the most abundant glial cells in the central nervous system and play important roles in both physiological and pathological conditions. Over the past few decades, a growing body of evidence indicates that astrocytes are involved in the regulation of chronic pain. Recently, reactive astrocytes were further classified into A1 astrocytes and A2 astrocytes according to their functions. After nerve injury, A1 astrocytes can secrete neurotoxins that induce rapid death of neurons and oligodendrocytes, whereas A2 astrocytes promote neuronal survival and tissue repair. These findings can well explain the dual effects of reactive astrocytes in central nervous injury and diseases. In this review, we will summarise the (1) changes in the morphology and function of astrocytes after noxious stimulation and nerve injury, (2) molecular regulators and signalling mechanisms involved in the activation of astrocytes and chronic pain, (3) the role of spinal and cortical astrocyte activation in chronic pain, and (4) the roles of different subtypes of reactive astrocytes (A1 and A2 phenotypes) in nerve injury that is associated with chronic pain. This review provides updated information on the role of astrocytes in the regulation of chronic pain. In particular, we discuss recent findings about A1 and A2 subtypes of reactive astrocytes and make several suggestions for potential therapeutic targets for chronic pain.

Keywords: A1 astrocytes; A2 astrocytes; Chronic pain; Cortical astrocytes; Reactive astrocytes.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Astrocyte functions in the CNS. Astrocytes play significant roles in the CNS physiology. AA, arachidonic acid; NO, nitric oxide; PG, prostaglandin; VEGF, vascular endothelial growth factor; GABA, γ-aminobutyric acid; BBB, blood–brain barrier
Fig. 2
Fig. 2
Changes in the morphology and function of astrocytes after noxious stimulation and nerve injury. Based on phenotypic changes of astrocytes, astrocyte can be divided into reactive and scar-forming astrocyte, reactive astrocyte can be further classified by A1 and A2 astrocyte. Based on functional changes of astrocyte, astrocytopathy can be divided into astrocytes atrophy with loss of function, pathological remodelling of astrocytes and reactive astrogliosis based on functional cellular responses
Fig. 3
Fig. 3
Molecular regulators and signalling mechanisms involved in the activation of astrocytes. The transformation of astrocytes from normal to reactive phenotypes involves a variety of intercellular and intracellular signalling mechanisms that trigger and maintain astrocytes reactivity.① Gp130-JAK-STAT3 signalling pathway. ② Notch-OLIG2 signalling pathway. ③ TGFβ-RGMa-SMAD signalling pathway. ④ Rac-GSPT1 signalling pathway. These signalling pathways regulate the expression of some genes that characterise reactive astrocytes, such as the genes that encode GFAP, CX43, and AQP4, and thus contribute to reactive astrogliosis. Furthermore, multiple signalling molecules in these signalling pathways promote the maintenance and development of chronic pain. IL, interleukin; LIF, leukaemia inhibitory factor; CNTF, ciliary neurotrophic factor; TGF-β, transforming growth factor-β; TNF-α, tumour necrosis factor-α; ET-1, endothelin-1; STAT3, signal transducer and activator of transcription 3; OLIG2, oligodendrocyte transcription factor 2; SMAD, Sma- and Mad-related protein; ROCK, rho associated kinase; GFAP, glial fibrillary acidic protein; CX43, connexin43; RII, type II receptor; ALK5, activatin-like kinase 5; JAK, janus kinase. GSPT1, G1 to S phase transition 1; RGMa, repulsive guidance molecule a
Fig. 4
Fig. 4
Activation of astrocytes has dual effects. Astrogliosis is a defence mechanism for repairing initial damage, but it can also have adverse effects
Fig. 5
Fig. 5
The role of cortical reactive astrocytes in chronic pain. Activated astrocytes in brain regions related to emotion regulation (the S1, ACC, medial prefrontal cortex, and hippocampus) are involved in both pain and pain-related emotional dysfunction. The imbalance between glutamate and GABA due to astrocyte activation in these regions may be one mechanism underlying chronic pain. ACC, anterior cingulate cortex; GAT-3, GABA transporters3; mGluR5, metabotropic glutamate receptor 5; mPFC, the medial prefrontal cortex; S1, somatosensory cortex; TSP-1, thrombospondin 1
Fig. 6
Fig. 6
The role of spinal reactive astrocytes in chronic pain. Astrocyte-microglia crosstalk and astrocyte-neuron crosstalk facilitate the development of chronic pain. For example, reactive astrocyte can receive multiple molecular signals from microglia as well as neuron and can secrete several of molecular signals that act on neuron and microglia thereby promoting the development of pain. TLR, toll-like receptor
Fig. 7
Fig. 7
The possible mechanism of A1 and A2 subtypes of reactive astrocytes in chronic pain. A1 reactive astrocytes may facilitate directly the development of chronic pain by releasing some molecules such as pro-inflammatory cytokines, chemokines, and intracellular kinases. It can also indirectly lead to chronic pain by inducing neuronal death. A2 astrocytes may inhibit the progression of chronic pain by secreting neuroprotective factors that promote neuronal survival

Similar articles

See all similar articles

Cited by 3 articles

References

    1. Nakagawa T, Kaneko S. Spinal astrocytes as therapeutic targets for pathological pain. J Pharmacol Sci. 2010;114(4):347–353. - PubMed
    1. Ji RR, Chamessian A, Zhang YQ. Pain regulation by non-neuronal cells and inflammation. Science. 2016;354(6312):572–577. - PMC - PubMed
    1. Ji R, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;129(2):343–366. - PMC - PubMed
    1. O’Callaghan JP, Miller DB. Spinal glia and chronic pain. Metabolism. 2010;59(Suppl 1):S21–S26. - PubMed
    1. Eto K, Kim SK, Takeda I, Nabekura J. The roles of cortical astrocytes in chronic pain and other brain pathologies. Neurosci Res. 2018;126:3–8. - PubMed
Feedback