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  • Review Article
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Pathological and protective roles of glia in chronic pain

Key Points

  • Pain processing involves neurons, microglia and astrocytes. The functions of glia extend beyond basic support for neurons. Once activated, they release various classic immune factors that are also neuroactive substances.

  • Glia express receptors for neurotransmitters and neuromodulators, so they can respond to neural activity.

  • Despite the integral part that glia play in neuronal communication, most of the drugs that are available for treating pathological pain in humans target neuronal mechanisms. This may be one reason for their limited therapeutic efficacy in pain control. Early evidence from preclinical studies with animal models of neuropathic pain suggest that shifting glial activation from a pro-inflammatory to an anti-inflammatory state may prove to be important in clinical pain phenomena.

  • Activated glia exert crucial neuroprotective and anti-inflammatory effects. Identifying ways to regulate the switch between the proinflammatory and the anti-inflammatory state of glial activation, rather than simply blocking glial actions, could be key to the development of more powerful strategies to treat clinical pain.

Abstract

Glia have emerged as key contributors to pathological and chronic pain mechanisms. On activation, both astrocytes and microglia respond to and release a number of signalling molecules, which have protective and/or pathological functions. Here we review the current understanding of the contribution of glia to pathological pain and neuroprotection, and how the protective, anti-inflammatory actions of glia are being harnessed to develop new drug targets for neuropathic pain control. Given the prevalence of chronic pain and the partial efficacy of current drugs, which exclusively target neuronal mechanisms, new strategies to manipulate neuron–glia interactions in pain processing hold considerable promise.

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Figure 1: Nociception.
Figure 2: Molecules involved in pain processing.
Figure 3: Glia activation: from pro-inflammatory to anti-inflammatory states.

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Acknowledgements

This work was supported by NIH grants: DA018156, DA015642 and DA015656.

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Correspondence to Erin D. Milligan.

Glossary

Acute pain

A sensation that results from a transient, high-intensity stimulation that exceeds a threshold for the activation of specialized nerve endings located on nociceptive sensory fibres; it often leads to tissue damage.

Pathological pain

Pain that is associated with inflammation and/or trauma of peripheral tissue or nerves after injury.

Neuropathic pain

Pathological pain that is often persistent and is produced by damage to peripheral nerves or by lesions of the CNS.

Cytokine

A chemical signal released by immune cells that significantly alters many cell types, including other immune cells.

Chemokine

A class of cytokine that was originally identified as having chemotactic properties. To date, 50 chemokines have been identified. Chemokines are classified according to the number and spacing of conserved cysteine residues in their amino termini.

Nociceptive neuron

A sensory neuron that specifically responds to noxious stimuli and contains a bifurcating axon, with one branch projecting to the periphery and the other to the CNS.

Dorsal root ganglia

(DRG). Clusters of primary sensory neurons of the peripheral somatosensory system. These ganglia are adjacent to the spinal cord and send axons to the dorsal horn of the spinal cord.

Spinal cord laminae

Laminae (also known as layers) of the spinal cord that are organized by the type of information that they receive from the body. Laminae I and II, located in the superficial portion of the dorsal spinal cord, receive information from peripheral afferent nociceptive fibres. Laminae III–VI receive information about non-noxious stimuli and proprioceptive information. Lamina V plays an important part in the transmission of noxious information to supra-spinal pain centres.

Chronic pain

Persistent pain with an indefinite duration. It can originate from tissue and/or nerve damage and becomes chronic pain when it is prolonged and no longer has a clearly defined underlying cause.

Blood–brain barrier

A unique, selective barrier that makes blood vessels in the CNS highly impermeable to substances carried in the blood stream. Drugs must be able to cross the blood–brain barrier in order to achieve therapeutic levels in the CNS.

Toll-like receptors

(TLRs). Pattern-recognition receptors expressed on cells of the innate immune system that recognize microbial particles, leading to clearance, cell death and inflammation.

Meninges

Three membranous layers (the dura mater, arachnoid mater and pia mater) that surround the spinal cord and cerebrospinal fluid space.

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Milligan, E., Watkins, L. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10, 23–36 (2009). https://doi.org/10.1038/nrn2533

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