Glia in pathological pain: A role for fractalkine

https://doi.org/10.1016/j.jneuroim.2008.04.011Get rights and content

Abstract

Microglia and/or astrocytes play a significant role in the creation and maintenance of exaggerated pain states with inflammatory and/or neuropathic etiologies. The chemokine, fractalkine, has several functions, including the newly recognized role of mediating neuropathic pain conditions. Although constitutively expressed and released during inflammation, increased release of fractalkine binds to and activates microglia leading to pathological pain. We review the critical role of fractalkine in neuron-to-glial communication after peripheral nerve injury and inflammation and explore anti-inflammatory cytokines like interleukin-10 as a novel and effective approach for clinical pain control.

Section snippets

Previously understood views of pain

Traditionally, our understanding about neuronal signaling for pain transmission from the body to the central nervous system (CNS) occurs as a series of relay signals that are eventually processed in the brain. These relay signals are thought to serve protective and adaptive roles, with the first synaptic relay, between the first order (sensory) neuron and the second order neuron in the dorsal horn of the spinal cord. Neurons that receive and respond to pain information are primarily located in

Glial modulation of neuronal activity

Glia act to dynamically regulate neuronal synaptic communication (Haydon, 2001), and can lead to pathological pain via the release of a variety of neurotransmitters, neuromodulators (McMahon et al., 2005), proinflammatory cytokines and chemokines (Rostene et al., 2007). Astrocytes are closely associated with neuronal somas, dendrites, and pre- and post-synaptic sites, as well as with other glia (microglia), and their functions are now understood to include active, integrative roles during

Evolving views of pain modulation: glia play a significant role in pathological pain states

Diverse animal models of nerve injury or inflammation, either peripherally or centrally, produce pathological pain states such as thermal hyperalgesia (exaggerated responses to painful heat) and mechanical allodynia (non-painful touch/pressure stimuli that become painful) (Zimmermann, 2001). These models have demonstrated the involvement of spinal cord glia which become activated with the development of pain enhancement. For example, pain produced by chronic constriction injury (CCI), a

Neuron-to-glia signals: neurotransmitters and neuromodulators

While a number of factors released spinal cord neurons and glia are known to sensitize neuron–glial interactions leading to pathological pain, the spinal glial response to trauma at distant locations is not fully understood. What are the neuron-to-glial signals that induce subsequent glial activation after peripheral inflammation or nerve trauma? As reviewed above, glia express functional receptors for many neurotransmitters and are able to respond to these signals (Pocock and Kettenmann, 2007

Neuron-to-glia signals: fractalkine

Neurotransmitters and neuromodulators are not the only substances neurons release that can trigger the activation of glia. Fractalkine is another factor released by neurons of the pain pathway, which has been documented to mediate pathological pain (Clark et al., 2007, Lindia et al., 2005, Milligan et al., 2004, Milligan et al., 2005c, Zhuang et al., 2007). Fractalkine, first discovered as neurotactin (Pan et al., 1997) is a chemokine, a term which refers to a family of over 50 proteins

Toll-like receptor signaling in chemokine-mediated pathological pain

Although fractalkine is responsible for the recruitment of natural killer cells during neurodegenerative conditions in animal models for MS or ALS, as well as mediates pain in animal models for neuropathic pain, other innate immune cells (leukocytes) and lymphocytes (T cells) are characterized to migrate into pain-relevant areas of the spinal cord during neuropathic pain conditions (Cao and Deleo, 2008, Sweitzer et al., 2002). The chemoattractant(s) responsible for spinal cord lymphocyte and

Targeting activated glia with anti-inflammatory cytokines to resolve pathological pain

Given chemokines like fractalkine act to attract cells to the site inflammatory activity, anti-inflammatory factors may dampen such signaling. Spinal anti-inflammatory treatment with interleukin-2 (IL-2), interleukin-4 (IL-4), transforming growth factor-beta (TGF-β) (Schafers and Sommer, 2007), and IL-10 (Moore et al., 2001) may prove beneficial. One approach for achieving sustained suppression of proinflammatory cytokine action is by utilizing gene delivery to the spinal cord. Gene-encoding

References (91)

  • HolguinA. et al.

    HIV-1 gp120 stimulates proinflammatory cytokine-mediated pain facilitation via activation of nitric oxide synthase-I (nNOS)

    Pain

    (2004)
  • HundhausenC. et al.

    The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell–cell adhesion

    Blood

    (2003)
  • LedeboerA. et al.

    Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation

    Pain

    (2005)
  • LedeboerA. et al.

    Intrathecal interleukin-10 gene therapy attenuates paclitaxel-induced mechanical allodynia and proinflammatory cytokine expression in dorsal root ganglia in rats

    Brain Behav. Immun.

    (2007)
  • LindiaJ.A. et al.

    Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain

    J. Pain

    (2005)
  • MalcangioM. et al.

    Effect of interleukin-1beta on the release of substance P from rat isolated spinal cord

    Eur. J. Pharmacol.

    (1996)
  • McMahonS.B. et al.

    Immune and glial cell factors as pain mediators and modulators

    Exp. Neurol.

    (2005)
  • MillanM.J.

    The induction of pain: an integrative review

    Prog. Neurobiol.

    (1999)
  • MilliganE.D. et al.

    Repeated intrathecal injections of plasmid DNA encoding interleukin-10 produce prolonged reversal of neuropathic pain

    Pain

    (2006)
  • OwolabiS.A. et al.

    Fractalkine and minocycline alter neuronal activity in the spinal cord dorsal horn

    FEBS Lett.

    (2006)
  • PlunkettJ.A. et al.

    Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat

    Exper. Neurol.

    (2001)
  • PocockJ.M. et al.

    Neurotransmitter receptors on microglia

    Trends Neurosci.

    (2007)
  • PorterJ.T. et al.

    Astrocytic neurotransmitter receptors in situ and in vivo

    Prog. Neurobiol.

    (1997)
  • RaghavendraV. et al.

    Anti-hyperalgesic and morphine-sparing actions of propentofylline following peripheral nerve injury in rats: mechanistic implications of spinal glia and proinflammatory cytokines

    Pain

    (2003)
  • RansohoffR.M. et al.

    Chemokines and chemokine receptors: multipurpose players in neuroinflammation

    Int. Rev. Neurobiol.

    (2007)
  • SouthallM.D. et al.

    Intrathecal NSAIDS attenuate inflammation-induced neuropeptide release from rat spinal cord slices

    Pain

    (1998)
  • SweitzerS.M. et al.

    Focal peripheral nerve injury induces leukocyte trafficking into the central nervous system: potential relationship to neuropathic pain

    Pain

    (2002)
  • WatkinsL.R. et al.

    Glial activation: a driving force for pathological pain

    Trends Neurosci.

    (2001)
  • YaoM.Z. et al.

    Interleukin-2 gene therapy of chronic neuropathic pain

    Neuroscience

    (2002)
  • YuC.-G. et al.

    Effects of agmatine, interleukin-10 and cyclosporin on spontaneous pain behavior following excitotoxic spinal cord injury in rats

    J. Pain

    (2003)
  • ZhuangZ.-Y. et al.

    Role of the CX3CR1/p38 MAPK pathway in spinal microglia for the development of neuropathic pain following nerve injury-induced cleavage of fractalkine

    Brain Behav. Immun.

    (2007)
  • ZimmermannM.

    Pathobiology of neuropathic pain

    Eur. J. Pharmacol.

    (2001)
  • AbrahamK.E. et al.

    The effects of endogenous interleukin-10 on gray matter damage and pain behaviors following excitotoxic spinal cord injury in the mouse

    Neuroscience

    (2004)
  • AimarP. et al.

    Nitric oxide-producing islet cells modulate the release of sensory neuropeptides in the rat substantia gelatinosa

    J. Neurosci.

    (1998)
  • AravalliR.N. et al.

    Toll-like receptors in defense and damage of the central nervous system

    J. Neuroimmune. Pharmacol.

    (2007)
  • BazanJ.F. et al.

    A new class of membrane-bound chemokine with CX3C motif

    Nature

    (1997)
  • BenvenisteE.N.

    Cytokine expression in the nervous system

  • CaoL. et al.

    CNS-infiltrating CD4+ T lymphocytes contribute to murine spinal nerve transection-induced neuropathic pain

    Eur. J. Immunol.

    (2008)
  • ChapmanG.A. et al.

    Fractalkine cleavage from neuronal membranes represents an acute event in the inflammatory response to excitotoxic brain damage

    J. Neurosci.

    (2000)
  • ClarkA.K. et al.

    Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain

    Proc. Natl. Acad. Sci.

    (2007)
  • CrossA.K. et al.

    Chemokine modulation of matrix metalloproteinase and TIMP production in adult rat brain microglia and a human microglial cell line in vitro

    Glia

    (1999)
  • FellinT. et al.

    Bidirectional astrocyte–neuron communication: the many roles of glutamate and ATP

  • FonnumF. et al.

    Use of fluorocitrate and fluoroacetate in the study of brain metabolism

    Glia

    (1997)
  • GuoL.-H. et al.

    The innate immunity of the central nervous system in chronic pain: the role of Toll-like receptors

    Cell. Mol. Life Sci.

    (2007)
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      Citation Excerpt :

      Fractalkine is a large cytokine in the CX3C chemokine family that is constitutively expressed in primary nociceptive neurons, including sensory neurons in the dorsal root ganglion (Souza et al., 2013). Fractalkine has been identified as a key cytokine in the manifestation of neuropathic pain, and has also been hypothesized to play a role in substance-induced hyperalgesia (Clark and Malcangio, 2014; Milligan et al., 2008; Souza et al., 2013). Satellite glial cells are found in the dorsal root ganglion where they protect sensory neurons by reacting to inflammatory damage by activating, proliferating, and releasing pro-inflammatory cytokines (Souza et al., 2013).

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