Astrocytes in chronic pain and itch

Abstract

Astrocytes are critical for maintaining the homeostasis of the CNS. Increasing evidence suggests that a number of neurological and neuropsychiatric disorders, including chronic pain, may result from astrocyte ‘gliopathy’. Indeed, in recent years there has been substantial progress in our understanding of how astrocytes can regulate nociceptive synaptic transmission via neuronal–glial and glial–glial cell interactions, as well as the involvement of spinal and supraspinal astrocytes in the modulation of pain signalling and the maintenance of neuropathic pain. A role of astrocytes in the pathogenesis of chronic itch is also emerging. These developments suggest that targeting the specific pathways that are responsible for astrogliopathy may represent a novel approach to develop therapies for chronic pain and chronic itch.

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Fig. 1: Homeostatic functions of astrocytes.
Fig. 2: Astrocyte–neuron and astrocyte–microglial cell interactions in neuropathic pain.
Fig. 3: Propagation of chronic itch through disinhibition and astrocyte activation.
Fig. 4: Future directions in the investigation of astrocytes in chronic pain.

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Acknowledgements

This work was supported by NIH grants DE17794, to R.-R.J., and DE22743, to R.-R.J. and M.N. M.N is also supported by the Lundbeck Foundation. C.R.D. is supported by a John J. Bonica Trainee Fellowship from the International Association for the Study of Pain and by NIH grant T32 GM08600.

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Correspondence to Ru-Rong Ji or Maiken Nedergaard.

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Glossary

Neuroinflammation

A localized form of inflammation occurring in the peripheral nervous system and/or CNS.

Central sensitization

Forms of neuronal and/or synaptic plasticity characterized by increased responsiveness of nociceptive neurons in the CNS to their normal input.

Hemichannels

Assemblies composed of six connexin proteins, which form a pore that allows for the bidirectional flow of ions and signalling molecules.

Glymphatic system

A waste clearance system in the CNS that utilizes a unique network of perivascular tunnels formed by astrocytes.

Cytokines

A large and diverse class of small (<30 kDa) proteins, glycoproteins and peptides that are secreted by cells and exert specific biological functions, including pain modulations.

Satellite glial cells

A cell type in the peripheral nervous system that is roughly equivalent in function to astrocytes in the CNS.

Allodynia

Pain in response to a stimulus that does not normally provoke pain. Mechanical allodynia is a cardinal feature of chronic pain.

Hyperalgesia

Increased pain in response to a stimulus that ordinarily provokes pain.

Optogenetic

The use of light to activate or inhibit genetically encoded ion channels expressed within a defined cell type of interest.

Chemokines

A specific family of immunomodulatory cytokines named for their ability to induce directed chemotaxis of immune effector cells.

Analgesia

The absence of pain in response to stimulation that would normally be painful.

Inflammasome

A multimeric intracellular signalling complex responsible for the detection of pathogenic microorganisms and host-derived stressors, leading to the activation of caspase-1 and the induction of inflammation.

Nociceptors

Specialized neurons of the somatosensory nervous system that are capable of transducing nociceptive stimuli.

Immunotherapeutic

A therapeutic agent used to treat a disease by activating or suppressing the immune system.

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Ji, R., Donnelly, C.R. & Nedergaard, M. Astrocytes in chronic pain and itch. Nat Rev Neurosci 20, 667–685 (2019). https://doi.org/10.1038/s41583-019-0218-1

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