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  • Review Article
  • Published:

Chemokines: Integrators of Pain and Inflammation

Nature Reviews Drug Discovery volume 4, pages 834–844 (2005)Cite this article

Key Points

  • Neuropathic pain syndromes refer to long-lasting 'pathological' states of increased pain intensity (hyperalgesia) or sensitivity (allodynia). These syndromes often result from damage to peripheral nerves, infection or the toxic effects of drugs.

  • Neuropathic pain states are characterized by increased excitability of sensory nociceptive (pain sensing) nerves, changes in the phenotypes of sensory nerves and enhanced synaptic transmission in the spinal cord. However, the cellular and molecular changes that result in these effects are not known. Here, we discuss the possibility that neuroinflammatory responses accompanying neuropathic pain increase the synthesis of molecules that result in pain hypersensitivity.

  • Chemokines (chemotactic cytokines) are small secreted proteins that produce their effects by stimulating G-protein-coupled receptors. There are four families of chemokines and four families of chemokine receptors. Some chemokine receptors, for example, CCR5 and CXCR4, have been shown to be the cellular receptors responsible for HIV-1 infection of target cells. Chemokines have been widely studied owing to their important role in regulating the trafficking of leukocytes under normal conditions and to sites of inflammation. Therefore, chemokines are considered to be major orchestrators of the inflammatory response.

  • Recent work has demonstrated that chemokines and their receptors are also expressed in the nervous system. Chemokines have various effects in the nervous system, ranging from the trafficking of stem cells during embryological development to effects on neuronal excitability and synaptic transmission. In particular, sensory nociceptive neurons express various chemokine receptors. Activation of these receptors by chemokines produces excitation of nociceptors through the transactivation of the TRPV1 (transient receptor potential vanilloid 1) capsaicin receptor, resulting in Na+ influx and neuronal depolarization. Intradermal application of several chemokines produces a strong pain response.

  • In some models of neuropathic pain, the chemokine (CC motif) receptor 2 (CCR2) and its major ligand the chemokine monocyte chemotactic protein-1 (MCP1; also known as CCL2) are upregulated by nociceptive neurons. In association with this, nociceptive neurons in neuropathic pain models are strongly excited by application of MCP1. CCR2-knockout mice show greatly reduced neuropathic pain responses. Therefore, it is possible that direct MCP1 excitation of nociceptive neurons is an important factor in the production of neuropathic pain responses.

  • Drugs that block chemokine receptors, such as CCR2, might constitute a novel class of therapeutic agents for the treatment of painful sensory neuropathies.

Abstract

Chronic (neuropathic) pain is one of the most widespread and intractable of human complaints, as well as being one of the most difficult syndromes to treat successfully with drugs or surgery. The development of new therapeutic approaches to the treatment of painful neuropathies requires a better understanding of the mechanisms that underlie the development of these chronic pain syndromes. It is clear that inflammatory responses often accompany the development of neuropathic pain, and here we discuss the idea that chemokines might be key to integrating the development of pain and inflammation and could furnish new leads in the search for effective analgesic agents for the treatment of painful neuropathies.

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Figure 1: Schematic diagram of peripheral nervous sytem.
Figure 2: Chemokine receptors expressed by cultured rat neonatal dorsal rat ganglia (DRG) neurons.
Figure 3: CCR2 mRNA expression in compressed and adjacent, non-compressed dorsal root ganglia (DRG).
Figure 4: Possible chemokine receptor function in the context of HIV-1 neuropathy.
Figure 5: Possible chemokine-mediated signal transduction in dorsal root ganglia neurons in association with neuropathic pain.

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Authors and Affiliations

  1. Department of Cell Biology, and Department of Anesthesiology, Neurobiology and Anatomy, Stritch School of Medicine, Loyola University, Maywood, 60153, Illinois, USA

    Fletcher A. White

  2. Department of Molecular Pharmacology and Structural Biochemistry, Northwestern University Medical School, 303 East Chicago Avenue, Chicago, 60611, Illinois, USA

    Sonia K. Bhangoo & Richard J. Miller

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Correspondence to Richard J. Miller.

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DATABASES

Entrez Gene

B1 receptor

B2 receptor

CCR1

CCR2

CCR5

CX3CL1

CX3CR1

CXCR1

CXCR2

CXCR3

CXCR4

IL-1β

IL-6

LIF

MCP1

RANTES

SDF1

TNFα

TRPV1

OMIM

Guillain–Barré syndrome

HIV-1

Glossary

GLIAL FIBRILLARY ACIDIC PROTEIN

(GFAP). Principle astrocyte intermediate filament that is upregulated in Schwann cells following injury. It is likely to play a direct role in the subsequent inflammatory response.

NOCICEPTORS

Sensory neurons that respond to pain and noxious stimulation.

PARATHESIAS

Abnormal or unpleasant sensations that result from injury to one or more nerves, often described by patients as numbness or as prickly, stinging or burning feelings.

MYELINOPATHY

The degeneration of myelin sheaths of neurons.

BRADYKININ

Small peptide of the kinin family that excites peripheral nerves and regulates the contraction of blood vessels and fluid transport by epithelia.

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White, F., Bhangoo, S. & Miller, R. Chemokines: Integrators of Pain and Inflammation. Nat Rev Drug Discov 4, 834–844 (2005). https://doi.org/10.1038/nrd1852

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