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  • Review Article
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GLIA: A novel drug discovery target for clinical pain

Nature Reviews Drug Discovery volume 2, pages 973–985 (2003)Cite this article

Key Points

  • Presently available drugs are ineffective in controlling clinical pain in most patients and abolish the pain in only few. It is suggested that this failure arises from the fact that these drugs were developed to target neurons, rather than spinal cord glia (astrocytes and microglia).

  • Until recently, glia were thought of simply as housekeepers for neurons, regulating the extracellular ionic environment and removing debris. Recently, it has become recognized that these glia dynamically modulate the function of neurons under both physiological and pathological conditions.

  • Glial activation has been demonstrated to be both necessary and sufficient for enhanced nociception (pain transmission) in every animal model tested to date.

  • Activated glia enhance pain via the release of a variety of neuroactive substances. Central to these effects is glial release of pro-inflammatory cytokines (tumor-necrosis factor, interleukin-1 (IL-1) and IL-6). These, in turn, activate a cascade of events leading to the release of a host of neuroexcitatory substances (such as nitric oxide, prostaglandins, growth factors, excitatory amino acids and so on).

  • In animal models, the following block/reverse changes in nociception in every animal model of clinical pain studied to date: disruption of glial activation (fluorocitrate and minocycline); pro-inflammatory cytokine antagonists (Kineret, Remicade, Enbrel); pro-inflammatory cytokine synthesis inhibitors (propentofylline, thalidomide); and disrupting pro-inflammatory cytokine signalling and synthesis (leflunomide, methotrexate, p38 MAP kinase, IL-10).

  • These studies strongly indicate that drug discovery should seriously consider targeting spinal cord glial activation as a broad-spectrum solution to presently unresolved clinical pain syndromes.

Abstract

In many clinical pain syndromes, painful sensations are greatly amplified so that normally innocuous sensations, such as light touch or warmth, are perceived as pain. Presently available drugs are ineffective in controlling such pain in most patients and abolish the pain in only few. Why do they fail? These drugs were developed to target neurons that transmit nociceptive ('pain') information. However, glia have recently been recognized as powerful modulators of nociception, and could hold the key to the control of clinical pain and present a new target for drug discovery. This review examines the evidence for glial regulation of nociception and pharmacological approaches that might successfully control glially driven clinical pain syndromes.

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Figure 1: Schematic of pain and pain modulation.
Figure 2: A historical look at glial involvement in pain.
Figure 3: Microglia, as well as astrocytes, are activated by manipulations that create enhanced nociception in animal models.
Figure 4: Neuron-to-glia communication.
Figure 5: Pro-inflammatory cytokines are constitutively expressed in an inactive precursor form, allowing rapid release.
Figure 6: One of the newest approaches to the treatment of pathological pain by the control of glial activation.

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Acknowledgements

Our laboratory is supported by grants from the National Institute on Drug Abuse, National Institute of Neurological Diseases and Stroke, and National Institute of Mental Health.

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Authors and Affiliations

  1. Department of Psychology and the Center for Neuroscience, University of Colorado at Boulder, Boulder, 80309-0345, Colorado, USA

    Linda R. Watkins & Steven F. Maier

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  1. Linda R. Watkins
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Correspondence to Linda R. Watkins.

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Competing interests

Linda Watkins has received a grant from Avigen for work related to IL-10 gene therapy.

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DATABASES

LocusLink

CX3CR1

Fractalkine

Online Mendelian Inheritance in Man

Alzheimer's disease

Crohn's disease

rheumatoid arthritis

Glossary

PAIN FACILITATION

Perceiving pain out of proportion to the initiating stimulus. Includes hyperalgesia and allodynia, below.

HYPERALGESIA

Perceiving stimuli as more painful than they would normally be.

ALLODYNIA

Perceiving normally non-painful stimuli as painful.

PHENOTYPE SHIFT

As used here, means that a neuron changes what neurotransmitter it produces and releases, creating a functional change in the pain transmission system.

GLIAL FIBRILLARY ACIDIC PROTEIN

(GFAP). An astrocyte-specific protein. Increases in GFAP are frequently used as a marker of astrocyte activation.

p38 MAP KINASE

An intracellular signalling cascade, activated in response to pro-inflammatory cytokine receptor binding. Activation of this cascade leads to production of pro-inflammatory cytokines.

IMMUNOCOMPETENT

Functioning similar to immune cells; that is, expressing receptors for bacteria/viruses and releasing pro-inflammatory cytokines and other immune cell products on activation.

NEUROPATHIC PAIN

Allodynia/hyperalgesia caused by inflammation of and/or trauma to peripheral nerves.

IL-6-NEUTRALIZING ANTIBODIES

Antibodies that bind to IL-6 and so prevent IL-6 from binding to its receptor.

PERI-SPINAL INJECTION

Administering a drug into the cerebrospinal fluid surrounding the spinal cord; also called 'intrathecal'.

SYNOVIAL TISSUES

Tissues encapsulating joints.

NUCLEAR FACTOR-κB

(NF-κB). A transcription factor that is constitutively expressed. Its activation leads (among other effects) to the production of pro-inflammatory cytokines. Although constitutively expressed, its ability to move to the nucleus to bind to DNA is tonically inhibited by binding of IκB.

INHIBITOR OF κB

(IκB). An inhibitor of NF-κB activation. It is binding to NF-κB that keeps this transcription factor from being able to move to the nucleus to activate messenger RNA transcription.

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Watkins, L., Maier, S. GLIA: A novel drug discovery target for clinical pain. Nat Rev Drug Discov 2, 973–985 (2003). https://doi.org/10.1038/nrd1251

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