Review Article| Volume 59, SUPPLEMENT 1, S21-S26, October 2010

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Spinal glia and chronic pain

  • James P. O'Callaghan
    Corresponding authors. James P. O'Callaghan, PhD, or Diane B. Miller, PhD, Health Effects Laboratory Division, TMBB-HELD, Mailstop L-3014, CDC-NIOSH, 1095 Willowdale Rd, Morgantown, WV 26505, USA. Tel.: +1 304 285 6079 (JPO) or +1 304 285 5732 (DBM); fax: +1 304 285 6220 (JPO) or +1 304 285 6266 (DBM).
    Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
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  • Diane B. Miller
    Corresponding authors. James P. O'Callaghan, PhD, or Diane B. Miller, PhD, Health Effects Laboratory Division, TMBB-HELD, Mailstop L-3014, CDC-NIOSH, 1095 Willowdale Rd, Morgantown, WV 26505, USA. Tel.: +1 304 285 6079 (JPO) or +1 304 285 5732 (DBM); fax: +1 304 285 6220 (JPO) or +1 304 285 6266 (DBM).
    Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Morgantown, WV 26505, USA
    Search for articles by this author


      Therapeutic management of chronic pain has not been widely successful owing to a lack of understanding of factors that initiate and maintain the chronic pain condition. Efforts to delineate the mechanisms underlying pain long have focused on neuronal elements of pain pathways, and both opiate- and non–opiate-based therapeutics are thought largely to target neurons. Abnormal neuronal activity at the level of spinal cord “pain centers” in the dorsal horn leads to hypersensitivity or a hyperalgesic response subsequent to the initial painful stimulus. Only recently has the experimental literature implicated nonneuronal elements in pain because of the realization that glial-derived signaling molecules can contribute to and modulate pain signaling in the spinal cord. Most notably, glial proinflammatory mediators within the dorsal horn of the spinal cord appear to contribute to self-perpetuating pain. Chronic pain is modeled experimentally through a variety of manipulations of sensory nerves including cutting, crushing, resection, and ligation. The cellular and molecular responses in the spinal cord due to these manipulations often reveal activation of 2 types of glia: microglia and astrocytes. The activation states of both microglia and astrocytes are complex and may be driven by underlying chronic neuropathology and/or a chronically “primed” condition that accounts for their contribution to chronic pain. Recent evidence even suggests that opioid tolerance and withdrawal hyperalgesia may be initiated and maintained via actions of microglia and astroglia. Together, these recent findings suggest that glia will serve as novel therapeutic targets for the treatment of chronic pain. To fully exploit glia as novel therapeutic targets will require a greater understanding of glial biology, as well as the identification of agents able to control the glial reactions involved in chronic pain, without interfering with beneficial glial functions.
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        • Brennan F.
        • Carr D.B.
        • Cousins M.
        Pain management: a fundamental human right.
        Pain Medicine. 2007; 105: 205-221
        • Colburn R.W.
        • Rickman A.J.
        • DeLeo J.A.
        The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior.
        Exp Neurol. 1999; 157: 289-304
        • Wieseler-Frank J.
        • Maier S.F.
        • Watkins L.R.
        Central proinflammatory cytokines and pain enhancement.
        Neurosignals. 2005; 14: 166-174
        • Milligan E.D.
        • Watkins L.R.
        Pathological and protective roles of glia in chronic pain.
        Nat Rev Neurosci. 2009; 10: 23-36
        • Watkins L.R.
        • Hutchinson M.R.
        • Ledeboer A.
        • Wieseler-Frank J.
        • Milligan E.D.
        • Maier S.F.
        Glia as the “bad guys”: implications for improving clinical pain control and the clinical utility of opioids.
        Brain Behav Immun. 2007; 21: 131-146
        • Watkins L.R.
        • Hutchinson M.R.
        • Rice K.C.
        • Maier S.F.
        The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia.
        Trends Pharmacol Sci. 2009; 30: 581-591
        • Hanisch U.K.
        • Kettenmann H.
        Microglia: active sensor and versatile effector cells in the normal and pathologic brain.
        Nat Neurosci. 2007; 10: 1387-1394
        • Costigan M.
        • Scholz J.
        • Woolf C.J.
        Neuropathic pain: a maladaptive response of the nervous system to damage.
        Annu Rev Neurosci. 2009; 32: 1-32
        • Fields R.D.
        New culprits in chronic pain.
        Sci Am. 2009; 301: 50-57
        • Ubogu E.E.
        • Cossoy M.B.
        • Ransohoff R.M.
        The expression and function of chemokines involved in CNS inflammation.
        Trends Pharmacol Sci. 2006; 27: 48-55
        • Kreutzberg G.W.
        Microglia: a sensor for pathological events in the CNS.
        Trends Neurosci. 1996; 19: 312-318
        • Sofroniew M.V.
        Molecular dissection of reactive astrogliosis and glial scar formation.
        Trends Neurosci. 2009; 32: 638-647
        • Sofroniew M.V.
        • Vinters H.V.
        Astrocytes: biology and pathology.
        Acta Neuropathol. 2010; 119: 7-35
        • Garrison C.J.
        • Dougherty P.M.
        • Kajander K.C.
        • Carlton S.M.
        Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury.
        Brain Res. 1991; 565: 1-7
        • Wang W.
        • Wang W.
        • Mei X.
        • Huang J.
        • Wei Y.
        • Wang Y.
        • et al.
        Crosstalk between spinal astrocytes and neurons in nerve injury-induced neuropathic pain.
        PLoS One. 2009; e6973: 4
        • Henneberger C.
        • Papouin T.
        • Oliet S.H.
        • Rusakov D.A.
        Long-term potentiation depends on release of d-serine from astrocytes.
        Nature. 2010; 463: 232-236
        • Kimelberg H.K.
        Functions of mature mammalian astrocytes: a current view.
        Neuroscientist. 2010; 16: 79-106
        • Zhang D.
        • Hu X.
        • Qian L.
        • O'Callaghan J.P.
        • Hong J.S.
        Astrogliosis in CNS pathologies: is there a role for microglia?.
        Mol Neurobiol. 2010; ([Epub ahead of print])
        • McMahon S.B.
        • Malcangio M.
        Current challenges in glia-pain biology.
        Neuron. 2009; 64: 46-54
        • Gehrmann J.
        • Matsumoto Y.
        • Kreutzberg G.W.
        Microglia: intrinsic immuneffector cell of the brain.
        Brain Res Brain Res Rev. 1995; 20: 269-287
        • Streit W.J.
        • Conde J.R.
        • Fendrick S.E.
        • Flanary B.E.
        • Mariani C.L.
        Role of microglia in the central nervous system's immune response.
        Neurosci Res. 2005; 27: 685-691
        • Neumann H.
        • Kotter M.R.
        • Franklin R.J.
        Debris clearance by microglia: an essential link between degeneration and regeneration.
        Brain. 2009; 132: 288-295
        • Buttini M.
        • Limonta S.
        • Boddeke H.W.
        Peripheral administration of lipopolysaccharide induces activation of microglial cells in rat brain.
        Neurochem Int. 1996; 29: 25-35
        • Eng L.F.
        • Ghirnikar R.S.
        • Lee Y.L.
        Glial fibrillary acidic protein: GFAP—thirty-one years (1969-2000).
        Neurochem Res. 2000; 25: 1439-1451
        • Svensson C.I.
        • Brodin E.
        Spinal astrocytes in pain processing: non-neuronal cells as therapeutic targets.
        Mol Interv. 2010; 10: 25-38
        • Kashon M.L.
        • Ross G.W.
        • O'Callaghan J.P.
        • Miller D.B.
        • Petrovich H.
        • Burchfiel C.M.
        • et al.
        Associations of cortical astrogliosis with cognitive performance and dementia status.
        J Alzheimers Dis. 2004; 6: 595-604
        • Schmued L.C.
        • Hopkins K.J.
        • Fluoro-jade B.
        A high affinity fluorescent marker for the localization of neuronal degeneration.
        Brain Res. 2000; 874: 123-130
        • Switzer R.C.
        Application of silver degeneration stains for neurotoxicity testing.
        Toxic Pathol. 2000; 28: 70-83
        • Perry V.H.
        • Cunningham C.
        • Holmes C.
        Systemic infections and inflammation affect chronic neurodegeneration.
        Nat Rev Immunol. 2007; 7: 161-167
        • Block M.L.
        • Hong J.S.
        Chronic microglial activation and progressive dopaminergic neurotoxicity.
        Biochem Soc Trans. 2007; 35: 1127-1132
        • Dantzer R.
        • O'Connor J.C.
        • Fruend G.C.
        • Johnson R.W.
        • Kelley K.W.
        From inflammation to sickness and depression: when the immune system subjugates the brain.
        Nat Rev Neurosci. 2008; 9: 46-56
        • Dilger R.N.
        • Johnson R.W.
        Aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system.
        J Leukoc Biol. 2008; 84: 932-939
        • Sparkman N.L.
        • Johnson R.W.
        Neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress.
        Neuroimmunomodulation. 2008; 15: 323-330
        • Alexander J.K.
        • Devries A.C.
        Stress exacerbates neuropathic pain via glucocorticoid and NMDA receptor activation.
        Brain Behav Immun. 2009; 23: 851-860
        • Song P.
        • Zhao Z.Q.
        The involvement of glial cells in the development of morphine tolerance.
        Neur Res. 2001; 39: 281-286
        • Chang G.
        • Chen L.
        • Mao J.
        Opioid tolerance and hyperalgesia.
        Med Clin North Am. 2007; 91: 199-211
        • Ossipov M.H.
        • Lai J.
        • King T.
        • Vanerah T.W.
        • Porreca F.
        Underlying mechanisms of pronociceptive consequences of prolonged morphine exposure.
        Biopolymers. 2005; 80: 319-324
        • Mika J.
        Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness.
        Pharmacol Rep. 2008; 60: 297-307
        • Cui Y.
        • Liao X.X.
        • Liu W.
        • Guo R.X.
        • Wu Z.Z.
        • Zhao C.M.
        • et al.
        A novel role of minocycline: attenuating morphine antinociceptive tolerance by inhibition of p38 MAPK in the activated spinal microglia.
        Brain Behav Immun. 2008; 22: 114-123
        • Kim D.S.
        • Figueroa K.W.
        • Li K.W.
        • Boroujerdi A.
        • Yolo T.
        • David Luo Z.
        Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acidic protein in maintenance of pain behaviors.
        Pain. 2009; 143: 114-122