Skip to main content

The Role of Glia in the Spinal Cord in Neuropathic and Inflammatory Pain

  • Chapter
Pain Control

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 227))

Abstract

Chronic pain, both inflammatory and neuropathic, is a debilitating condition in which the pain experience persists after the painful stimulus has resolved. The efficacy of current treatment strategies using opioids, NSAIDS and anticonvulsants is limited by the extensive side effects observed in patients, underlining the necessity for novel therapeutic targets. Preclinical models of chronic pain have recently provided evidence for a critical role played by glial cells in the mechanisms underlying the chronicity of pain, both at the site of damage in the periphery and in the dorsal horn of the spinal cord. Here microglia and astrocytes respond to the increased input from the periphery and change morphology, increase in number and release pro-nociceptive mediators such as ATP, cytokines and chemokines. These gliotransmitters can sensitise neurons by activation of their cognate receptors thereby contributing to central sensitization which is fundamental for the generation of allodynia, hyperalgesia and spontaneous pain.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Agalave NM, Larsson M, Abdelmoaty S, Su J, Baharpoor A, Lundback P, Palmblad K, Andersson U, Harris H, Svensson CI (2014) Spinal HMGB1 induces TLR4-mediated long-lasting hypersensitivity and glial activation and regulates pain-like behavior in experimental arthritis. Pain 155(9):1802–1813

    CAS  PubMed  Google Scholar 

  • Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM (2011) Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 14:1142–1149

    CAS  PubMed  Google Scholar 

  • Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzman RJ (2005) Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain 116:213–219

    CAS  PubMed  Google Scholar 

  • Arruda JL, Colburn RW, Rickman AJ, Rutkowski MD, DeLeo JA (1998) Increase of interleukin-6 mRNA in the spinal cord following peripheral nerve injury in the rat: potential role of IL-6 in neuropathic pain. Brain Res Mol Brain Res 62:228–235

    CAS  PubMed  Google Scholar 

  • Backonja MM, Coe CL, Muller DA, Schell K (2008) Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients. J Neuroimmunol 195:157–163

    CAS  PubMed  Google Scholar 

  • Bas DB, Su J, Sandor K, Agalave NM, Lundberg J, Codeluppi S, Baharpoor A, Nandakumar KS, Holmdahl R, Svensson CI (2012) Collagen antibody-induced arthritis evokes persistent pain with spinal glial involvement and transient prostaglandin dependency. Arthritis Rheum 64:3886–3896

    CAS  PubMed  Google Scholar 

  • Bas DB, Abdelmoaty S, Sandor K, Codeluppi S, Fitzsimmons B, Steinauer J, Hua XY, Yaksh TL, Svensson CI (2015) Spinal release of tumour necrosis factor activates c-Jun N-terminal kinase and mediates inflammation-induced hypersensitivity. Eur J Pain 19(2):260–270

    PubMed Central  CAS  PubMed  Google Scholar 

  • Baudier J, Glasser N, Gerard D (1986) Ions binding to S100 proteins. I. Calcium- and zinc-binding properties of bovine brain S100 alpha alpha, S100a (alpha beta), and S100b (beta beta) protein: Zn2+ regulates Ca2+ binding on S100b protein. J Biol Chem 261:8192–8203

    CAS  PubMed  Google Scholar 

  • Bazan JF, Bacon KB, Hardiman G, Wang W, Soo K, Rossi D, Greaves DR, Zlotnik A, Schall TJ (1997) A new class of membrane-bound chemokine with a CX3C motif. Nature 385:640–644

    CAS  PubMed  Google Scholar 

  • Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:16021–16026

    PubMed Central  CAS  PubMed  Google Scholar 

  • Bodmer JL, Schneider P, Tschopp J (2002) The molecular architecture of the TNF superfamily. Trends Biochem Sci 27:19–26

    CAS  PubMed  Google Scholar 

  • Boettger MK, Weber K, Grossmann D, Gajda M, Bauer R, Bar KJ, Schulz S, Voss A, Geis C, Brauer R, Schaible HG (2010) Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation. Arthritis Rheum 62:1308–1318

    CAS  PubMed  Google Scholar 

  • Boyle DL, Jones TL, Hammaker D, Svensson CI, Rosengren S, Albani S, Sorkin L, Firestein GS (2006) Regulation of peripheral inflammation by spinal p38 MAP kinase in rats. PLoS Med 3:e338

    PubMed Central  PubMed  Google Scholar 

  • Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL (2014) Identification of a unique TGF-beta-dependent molecular and functional signature in microglia. Nat Neurosci 17:131–143

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cardona AE, Pioro EP, Sasse ME, Kostenko V, Cardona SM, Dijkstra IM, Huang D, Kidd G, Dombrowski S, Dutta R, Lee JC, Cook DN, Jung S, Lira SA, Littman DR, Ransohoff RM (2006) Control of microglial neurotoxicity by the fractalkine receptor. Nat Neurosci 9:917–924

    CAS  PubMed  Google Scholar 

  • Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B (1975) An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 72:3666–3670

    PubMed Central  CAS  PubMed  Google Scholar 

  • Cheunsuang O, Morris R (2000) Spinal lamina I neurons that express neurokinin 1 receptors: morphological analysis. Neuroscience 97:335–345

    CAS  PubMed  Google Scholar 

  • Christianson CA, Corr M, Firestein GS, Mobargha A, Yaksh TL, Svensson CI (2010) Characterization of the acute and persistent pain state present in K/BxN serum transfer arthritis. Pain 151:394–403

    PubMed Central  CAS  PubMed  Google Scholar 

  • Christianson CA, Dumlao DS, Stokes JA, Dennis EA, Svensson CI, Corr M, Yaksh TL (2011) Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain 152:2881–2891

    PubMed Central  CAS  PubMed  Google Scholar 

  • Clark AK, Malcangio M (2012) Microglial signalling mechanisms: Cathepsin S and Fractalkine. Exp Neurol 234:283–292

    CAS  PubMed  Google Scholar 

  • Clark AK, D’Aquisto F, Gentry C, Marchand F, McMahon SB, Malcangio M (2006) Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. J Neurochem 99:868–880

    CAS  PubMed  Google Scholar 

  • Clark AK, Gentry C, Bradbury EJ, McMahon SB, Malcangio M (2007a) Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain 11:223–230

    PubMed  Google Scholar 

  • Clark AK, Yip PK, Grist J, Gentry C, Staniland AA, Marchand F, Dehvari M, Wotherspoon G, Winter J, Ullah J, Bevan S, Malcangio M (2007b) Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proc Natl Acad Sci U S A 104:10655–10660

    PubMed Central  CAS  PubMed  Google Scholar 

  • Clark AK, Yip PK, Malcangio M (2009) The liberation of fractalkine in the dorsal horn requires microglial cathepsin S. J Neurosci 29:6945–6954

    PubMed Central  CAS  PubMed  Google Scholar 

  • Clark AK, Staniland AA, Marchand F, Kaan TK, McMahon SB, Malcangio M (2010) P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J Neurosci 30:573–582

    PubMed Central  CAS  PubMed  Google Scholar 

  • Clark AK, Staniland AA, Malcangio M (2011) Fractalkine/CX3CR1 signalling in chronic pain and inflammation. Curr Pharm Biotechnol 12:1707–1714

    CAS  PubMed  Google Scholar 

  • Clark AK, Grist J, Al-Kashi A, Perretti M, Malcangio M (2012) Spinal cathepsin S and fractalkine contribute to chronic pain in the collagen-induced arthritis model. Arthritis Rheum 64:2038–2047

    CAS  PubMed  Google Scholar 

  • Clark AK, Old EA, Malcangio M (2013) Neuropathic pain and cytokines: current perspectives. J Pain Res 6:803–814

    PubMed Central  PubMed  Google Scholar 

  • Colburn RW, Rickman AJ, DeLeo JA (1999) The effect of site and type of nerve injury on spinal glial activation and neuropathic pain behavior. Exp Neurol 157:289–304

    CAS  PubMed  Google Scholar 

  • Copray JC, Mantingh I, Brouwer N, Biber K, Kust BM, Liem RS, Huitinga I, Tilders FJ, Van Dam AM, Boddeke HW (2001) Expression of interleukin-1 beta in rat dorsal root ganglia. J Neuroimmunol 118:203–211

    CAS  PubMed  Google Scholar 

  • Corcione A, Ferretti E, Bertolotto M, Fais F, Raffaghello L, Gregorio A, Tenca C, Ottonello L, Gambini C, Furtado G, Lira S, Pistoia V (2009) CX3CR1 is expressed by human B lymphocytes and mediates [corrected] CX3CL1 driven chemotaxis of tonsil centrocytes. PLoS One 4:e8485

    PubMed Central  PubMed  Google Scholar 

  • Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, De Koninck Y (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021

    CAS  PubMed  Google Scholar 

  • Cox JJ, Reimann F, Nicholas AK, Thornton G, Roberts E, Springell K, Karbani G, Jafri H, Mannan J, Raashid Y, Al-Gazali L, Hamamy H, Valente EM, Gorman S, Williams R, McHale DP, Wood JN, Gribble FM, Woods CG (2006) An SCN9A channelopathy causes congenital inability to experience pain. Nature 444:894–898

    CAS  PubMed  Google Scholar 

  • D’Mello R, Dickenson AH (2008) Spinal cord mechanisms of pain. Br J Anaesth 101:8–16

    PubMed  Google Scholar 

  • Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8:752–758

    CAS  PubMed  Google Scholar 

  • Del Rio-Hortega P (1932) Microglia. In: Penfield W (ed) Cytology and cellular pathology of the nervous system. Hoeber, New York, pp 482–534

    Google Scholar 

  • Del Rio-Hortega P (2012a) Are the glia with very few processes homologous with Schwann cells? by Pio del Rio-Hortega. 1922. Clin Neuropathol 31:460–462

    PubMed  Google Scholar 

  • Del Rio-Hortega P (2012b) Studies on neuroglia: glia with very few processes (oligodendroglia) by PA-o del RA-o-Hortega. 1921. Clin Neuropathol 31:440–459

    PubMed  Google Scholar 

  • DeLeo JA, Colburn RW, Rickman AJ (1997) Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. Brain Res 759:50–57

    CAS  PubMed  Google Scholar 

  • Deloulme JC, Raponi E, Gentil BJ, Bertacchi N, Marks A, Labourdette G, Baudier J (2004) Nuclear expression of S100B in oligodendrocyte progenitor cells correlates with differentiation toward the oligodendroglial lineage and modulates oligodendrocytes maturation. Mol Cell Neurosci 27:453–465

    CAS  PubMed  Google Scholar 

  • Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87:2095–2147

    CAS  PubMed  Google Scholar 

  • Dinarello CA (2007) Historical insights into cytokines. Eur J Immunol 37(Suppl 1):S34–S45

    PubMed Central  CAS  PubMed  Google Scholar 

  • Dray A (2008) New horizons in pharmacologic treatment for rheumatic disease pain. Rheum Dis Clin North Am 34:481–505

    PubMed  Google Scholar 

  • Dunn E, Sims JE, Nicklin MJ, O’Neill LA (2001) Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol 22:533–536

    CAS  PubMed  Google Scholar 

  • Fong AM, Robinson LA, Steeber DA, Tedder TF, Yoshie O, Imai T, Patel DD (1998) Fractalkine and CX3CR1 mediate a novel mechanism of leukocyte capture, firm adhesion, and activation under physiologic flow. J Exp Med 188:1413–1419

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gao YJ, Ji RR (2010) Targeting astrocyte signaling for chronic pain. Neurotherapeutics 7:482–493

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gao YJ, Zhang L, Samad OA, Suter MR, Yasuhiko K, Xu ZZ, Park JY, Lind AL, Ma Q, Ji RR (2009) JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 29:4096–4108

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gao YJ, Xu ZZ, Liu YC, Wen YR, Decosterd I, Ji RR (2010a) The c-Jun N-terminal kinase 1 (JNK1) in spinal astrocytes is required for the maintenance of bilateral mechanical allodynia under a persistent inflammatory pain condition. Pain 148:309–319

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gao YJ, Zhang L, Ji RR (2010b) Spinal injection of TNF-alpha-activated astrocytes produces persistent pain symptom mechanical allodynia by releasing monocyte chemoattractant protein-1. Glia 58:1871–1880

    PubMed Central  PubMed  Google Scholar 

  • Garrison CJ, Dougherty PM, Kajander KC, Carlton SM (1991) Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 565:1–7

    CAS  PubMed  Google Scholar 

  • George A, Schmidt C, Weishaupt A, Toyka KV, Sommer C (1999) Serial determination of tumor necrosis factor-alpha content in rat sciatic nerve after chronic constriction injury. Exp Neurol 160:124–132

    CAS  PubMed  Google Scholar 

  • Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845

    PubMed Central  CAS  PubMed  Google Scholar 

  • Go VL, Yaksh TL (1987) Release of substance P from the cat spinal cord. J Physiol 391:141–167

    PubMed Central  CAS  PubMed  Google Scholar 

  • Gruber-Schoffnegger D, Drdla-Schutting R, Honigsperger C, Wunderbaldinger G, Gassner M, Sandkuhler J (2013) Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-alpha and IL-1beta is mediated by glial cells. J Neurosci 33:6540–6551

    CAS  PubMed  Google Scholar 

  • Guo W, Wang H, Watanabe M, Shimizu K, Zou S, LaGraize SC, Wei F, Dubner R, Ren K (2007) Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27:6006–6018

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hachem S, Aguirre A, Vives V, Marks A, Gallo V, Legraverend C (2005) Spatial and temporal expression of S100B in cells of oligodendrocyte lineage. Glia 51:81–97

    CAS  PubMed  Google Scholar 

  • Hao S, Mata M, Glorioso JC, Fink DJ (2007) Gene transfer to interfere with TNFalpha signaling in neuropathic pain. Gene Ther 14:1010–1016

    CAS  PubMed  Google Scholar 

  • Harrison JK, Jiang Y, Chen S, Xia Y, Maciejewski D, McNamara RK, Streit WJ, Salafranca MN, Adhikari S, Thompson DA, Botti P, Bacon KB, Feng L (1998) Role for neuronally derived fractalkine in mediating interactions between neurons and CX3CR1-expressing microglia. Proc Natl Acad Sci U S A 95:10896–10901

    PubMed Central  CAS  PubMed  Google Scholar 

  • Hathway GJ, Vega-Avelaira D, Moss A, Ingram R, Fitzgerald M (2009) Brief, low frequency stimulation of rat peripheral C-fibres evokes prolonged microglial-induced central sensitization in adults but not in neonates. Pain 144:110–118

    PubMed Central  PubMed  Google Scholar 

  • Hess A, Axmann R, Rech J, Finzel S, Heindl C, Kreitz S, Sergeeva M, Saake M, Garcia M, Kollias G, Straub RH, Sporns O, Doerfler A, Brune K, Schett G (2011) Blockade of TNF-alpha rapidly inhibits pain responses in the central nervous system. Proc Natl Acad Sci U S A 108:3731–3736

    PubMed Central  CAS  PubMed  Google Scholar 

  • Honda S, Sasaki Y, Ohsawa K, Imai Y, Nakamura Y, Inoue K, Kohsaka S (2001) Extracellular ATP or ADP induce chemotaxis of cultured microglia through Gi/o-coupled P2Y receptors. J Neurosci 21:1975–1982

    CAS  PubMed  Google Scholar 

  • Hughes PM, Botham MS, Frentzel S, Mir A, Perry VH (2002) Expression of fractalkine (CX3CL1) and its receptor, CX3CR1, during acute and chronic inflammation in the rodent CNS. Glia 37:314–327

    PubMed  Google Scholar 

  • Hundhausen C, Misztela D, Berkhout TA, Broadway N, Saftig P, Reiss K, Hartmann D, Fahrenholz F, Postina R, Matthews V, Kallen KJ, Rose-John S, Ludwig A (2003) The disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesion. Blood 102:1186–1195

    CAS  PubMed  Google Scholar 

  • Hundhausen C, Schulte A, Schulz B, Andrzejewski MG, Schwarz N, von Hundelshausen P, Winter U, Paliga K, Reiss K, Saftig P, Weber C, Ludwig A (2007) Regulated shedding of transmembrane chemokines by the disintegrin and metalloproteinase 10 facilitates detachment of adherent leukocytes. J Immunol 178:8064–8072

    CAS  PubMed  Google Scholar 

  • Imai T, Hieshima K, Haskell C, Baba M, Nagira M, Nishimura M, Kakizaki M, Takagi S, Nomiyama H, Schall TJ, Yoshie O (1997) Identification and molecular characterization of fractalkine receptor CX3CR1, which mediates both leukocyte migration and adhesion. Cell 91:521–530

    CAS  PubMed  Google Scholar 

  • Imamoto K, Leblond CP (1978) Radioautographic investigation of gliogenesis in the corpus callosum of young rats. II. Origin of microglial cells. J Comp Neurol 180:139–163

    CAS  PubMed  Google Scholar 

  • Inglis JJ, Notley CA, Essex D, Wilson AW, Feldmann M, Anand P, Williams R (2007) Collagen-induced arthritis as a model of hyperalgesia: functional and cellular analysis of the analgesic actions of tumor necrosis factor blockade. Arthritis Rheum 56:4015–4023

    PubMed  Google Scholar 

  • Ji RR, Gereau RW, Malcangio M, Strichartz GR (2009) MAP kinase and pain. Brain Res Rev 60:135–148

    PubMed Central  CAS  PubMed  Google Scholar 

  • Jung S, Aliberti J, Graemmel P, Sunshine MJ, Kreutzberg GW, Sher A, Littman DR (2000) Analysis of fractalkine receptor CX(3)CR1 function by targeted deletion and green fluorescent protein reporter gene insertion. Mol Cell Biol 20:4106–4114

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kawasaki Y, Zhang L, Cheng JK, Ji RR (2008) Cytokine mechanisms of central sensitization: distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28:5189–5194

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461–553

    CAS  PubMed  Google Scholar 

  • Kidd BL, Langford RM, Wodehouse T (2007) Arthritis and pain. Current approaches in the treatment of arthritic pain. Arthritis Res Ther 9:214

    PubMed Central  PubMed  Google Scholar 

  • Kim DS, Figueroa KW, Li KW, Boroujerdi A, Yolo T, Luo ZD (2009) 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 [corrected]. Pain 143:114–122

    PubMed Central  CAS  PubMed  Google Scholar 

  • Kim KW, Vallon-Eberhard A, Zigmond E, Farache J, Shezen E, Shakhar G, Ludwig A, Lira SA, Jung S (2011) In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. Blood 118:e156–e167

    CAS  PubMed  Google Scholar 

  • King IL, Dickendesher TL, Segal BM (2009) Circulating Ly-6C+ myeloid precursors migrate to the CNS and play a pathogenic role during autoimmune demyelinating disease. Blood 113:3190–3197

    PubMed Central  CAS  PubMed  Google Scholar 

  • Koeglsperger T, Li S, Brenneis C, Saulnier JL, Mayo L, Carrier Y, Selkoe DJ, Weiner HL (2013) Impaired glutamate recycling and GluN2B-mediated neuronal calcium overload in mice lacking TGF-beta1 in the CNS. Glia 61:985–1002

    PubMed Central  PubMed  Google Scholar 

  • Konig C, Zharsky M, Moller C, Schaible HG, Ebersberger A (2014) Involvement of peripheral and spinal tumor necrosis factor alpha in spinal cord hyperexcitability during knee joint inflammation in rats. Arthritis Rheumatol 66:599–609

    PubMed  Google Scholar 

  • Kuner R (2010) Central mechanisms of pathological pain. Nat Med 16:1258–1266

    CAS  PubMed  Google Scholar 

  • Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10:895–926

    PubMed Central  PubMed  Google Scholar 

  • Lawson LJ, Perry VH, Gordon S (1992) Turnover of resident microglia in the normal adult mouse brain. Neuroscience 48:405–415

    CAS  PubMed  Google Scholar 

  • Lee KM, Jeon SM, Cho HJ (2009) Tumor necrosis factor receptor 1 induces interleukin-6 upregulation through NF-kappaB in a rat neuropathic pain model. Eur J Pain 13:794–806

    CAS  PubMed  Google Scholar 

  • Lee KM, Jeon SM, Cho HJ (2010) Interleukin-6 induces microglial CX3CR1 expression in the spinal cord after peripheral nerve injury through the activation of p38 MAPK. Eur J Pain 14:682.e1–e12

    Google Scholar 

  • Leung L, Cahill CM (2010) TNF-alpha and neuropathic pain—a review. J Neuroinflammation 7:27

    PubMed Central  PubMed  Google Scholar 

  • Lever IJ, Grant AD, Pezet S, Gerard NP, Brain SD, Malcangio M (2003) Basal and activity-induced release of substance P from primary afferent fibres in NK1 receptor knockout mice: evidence for negative feedback. Neuropharmacology 45:1101–1110

    CAS  PubMed  Google Scholar 

  • Levison SW, Goldman JE (1993) Both oligodendrocytes and astrocytes develop from progenitors in the subventricular zone of postnatal rat forebrain. Neuron 10:201–212

    CAS  PubMed  Google Scholar 

  • Levison SW, Goldman JE (1997) Multipotential and lineage restricted precursors coexist in the mammalian perinatal subventricular zone. J Neurosci Res 48:83–94

    CAS  PubMed  Google Scholar 

  • Levison SW, Chuang C, Abramson BJ, Goldman JE (1993) The migrational patterns and developmental fates of glial precursors in the rat subventricular zone are temporally regulated. Development 119:611–622

    CAS  PubMed  Google Scholar 

  • Liaw WJ, Stephens RL Jr, Binns BC, Chu Y, Sepkuty JP, Johns RA, Rothstein JD, Tao YX (2005) Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 115:60–70

    CAS  PubMed  Google Scholar 

  • Lindia JA, McGowan E, Jochnowitz N, Abbadie C (2005) Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. J Pain 6:434–438

    CAS  PubMed  Google Scholar 

  • Ling EA, Penney D, Leblond CP (1980) Use of carbon labeling to demonstrate the role of blood monocytes as precursors of the ‘ameboid cells’ present in the corpus callosum of postnatal rats. J Comp Neurol 193:631–657

    CAS  PubMed  Google Scholar 

  • Lister MF, Sharkey J, Sawatzky DA, Hodgkiss JP, Davidson DJ, Rossi AG, Finlayson K (2007) The role of the purinergic P2X7 receptor in inflammation. J Inflamm (Lond) 4:5

    Google Scholar 

  • Liu YL, Zhou LJ, Hu NW, Xu JT, Wu CY, Zhang T, Li YY, Liu XG (2007) Tumor necrosis factor-alpha induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with nerve injury: the role of NF-kappa B, JNK and p38 MAPK. Neuropharmacology 52:708–715

    CAS  PubMed  Google Scholar 

  • Liu T, Jiang CY, Fujita T, Luo SW, Kumamoto E (2013) Enhancement by interleukin-1beta of AMPA and NMDA receptor-mediated currents in adult rat spinal superficial dorsal horn neurons. Mol Pain 9:16

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liuzzo JP, Petanceska SS, Devi LA (1999a) Neurotrophic factors regulate cathepsin S in macrophages and microglia: a role in the degradation of myelin basic protein and amyloid beta peptide. Mol Med 5:334–343

    PubMed Central  CAS  PubMed  Google Scholar 

  • Liuzzo JP, Petanceska SS, Moscatelli D, Devi LA (1999b) Inflammatory mediators regulate cathepsin S in macrophages and microglia: a role in attenuating heparan sulfate interactions. Mol Med 5:320–333

    PubMed Central  CAS  PubMed  Google Scholar 

  • Lyons A, Lynch AM, Downer EJ, Hanley R, O’Sullivan JB, Smith A, Lynch MA (2009) Fractalkine-induced activation of the phosphatidylinositol-3 kinase pathway attentuates microglial activation in vivo and in vitro. J Neurochem 110:1547–1556

    CAS  PubMed  Google Scholar 

  • Malcangio M, Bowery NG (1994) Spinal cord SP release and hyperalgesia in monoarthritic rats: involvement of the GABAB receptor system. Br J Pharmacol 113:1561–1566

    PubMed Central  CAS  PubMed  Google Scholar 

  • Marchand F, Tsantoulas C, Singh D, Grist J, Clark AK, Bradbury EJ, McMahon SB (2009) Effects of Etanercept and Minocycline in a rat model of spinal cord injury. Eur J Pain 13:673–681

    CAS  PubMed  Google Scholar 

  • Marin-Teva JL, Dusart I, Colin C, Gervais A, Van RN, Mallat M (2004) Microglia promote the death of developing Purkinje cells. Neuron 41:535–547

    CAS  PubMed  Google Scholar 

  • Marin-Teva JL, Cuadros MA, Martin-Oliva D, Navascues J (2011) Microglia and neuronal cell death. Neuron Glia Biol 7:25–40

    PubMed  Google Scholar 

  • Martinon F, Burns K, Tschopp J (2002) The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 10:417–426

    CAS  PubMed  Google Scholar 

  • McKercher SR, Torbett BE, Anderson KL, Henkel GW, Vestal DJ, Baribault H, Klemsz M, Feeney AJ, Wu GE, Paige CJ, Maki RA (1996) Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J 15:5647–5658

    PubMed Central  CAS  PubMed  Google Scholar 

  • McMahon SB, Malcangio M (2009) Current challenges in glia-pain biology. Neuron 64:46–54

    CAS  PubMed  Google Scholar 

  • Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF (1994) The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 33:1471–1478

    CAS  PubMed  Google Scholar 

  • Milligan ED, Twining C, Chacur M, Biedenkapp J, O’Connor K, Poole S, Tracey K, Martin D, Maier SF, Watkins LR (2003) Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 23:1026–1040

    CAS  PubMed  Google Scholar 

  • Milligan ED, Zapata V, Chacur M, Schoeniger D, Biedenkapp J, O’Connor KA, Verge GM, Chapman G, Green P, Foster AC, Naeve GS, Maier SF, Watkins LR (2004) Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci 20:2294–2302

    CAS  PubMed  Google Scholar 

  • Milligan E, Zapata V, Schoeniger D, Chacur M, Green P, Poole S, Martin D, Maier SF, Watkins LR (2005a) An initial investigation of spinal mechanisms underlying pain enhancement induced by fractalkine, a neuronally released chemokine. Eur J Neurosci 22:2775–2782

    CAS  PubMed  Google Scholar 

  • Milligan ED, Langer SJ, Sloane EM, He L, Wieseler-Frank J, O’Connor K, Martin D, Forsayeth JR, Maier SF, Johnson K, Chavez RA, Leinwand LA, Watkins LR (2005b) Controlling pathological pain by adenovirally driven spinal production of the anti-inflammatory cytokine, interleukin-10. Eur J Neurosci 21:2136–2148

    PubMed  Google Scholar 

  • Milligan ED, Soderquist RG, Malone SM, Mahoney JH, Hughes TS, Langer SJ, Sloane EM, Maier SF, Leinwand LA, Watkins LR, Mahoney MJ (2006) Intrathecal polymer-based interleukin-10 gene delivery for neuropathic pain. Neuron Glia Biol 2:293–308

    PubMed Central  PubMed  Google Scholar 

  • Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K (2008) Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 28:12775–12787

    CAS  PubMed  Google Scholar 

  • Mizuno T, Kawanokuchi J, Numata K, Suzumura A (2003) Production and neuroprotective functions of fractalkine in the central nervous system. Brain Res 979:65–70

    CAS  PubMed  Google Scholar 

  • Nadeau S, Filali M, Zhang J, Kerr BJ, Rivest S, Soulet D, Iwakura Y, de Rivero Vaccari JP, Keane RW, Lacroix S (2011) Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1beta and TNF: implications for neuropathic pain. J Neurosci 31:12533–12542

    CAS  PubMed  Google Scholar 

  • Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308:1314–1318

    CAS  PubMed  Google Scholar 

  • Nishiyori A, Minami M, Ohtani Y, Takami S, Yamamoto J, Kawaguchi N, Kume T, Akaike A, Satoh M (1998) Localization of fractalkine and CX3CR1 mRNAs in rat brain: does fractalkine play a role in signaling from neuron to microglia? FEBS Lett 429:167–172

    CAS  PubMed  Google Scholar 

  • Ohtori S, Takahashi K, Moriya H, Myers RR (2004) TNF-alpha and TNF-alpha receptor type 1 upregulation in glia and neurons after peripheral nerve injury: studies in murine DRG and spinal cord. Spine (Phila Pa 1976) 29:1082–1088

    Google Scholar 

  • Okada-Ogawa A, Suzuki I, Sessle BJ, Chiang CY, Salter MW, Dostrovsky JO, Tsuboi Y, Kondo M, Kitagawa J, Kobayashi A, Noma N, Imamura Y, Iwata K (2009) Astroglia in medullary dorsal horn (trigeminal spinal subnucleus caudalis) are involved in trigeminal neuropathic pain mechanisms. J Neurosci 29:11161–11171

    PubMed Central  CAS  PubMed  Google Scholar 

  • Oku R, Satoh M, Fujii N, Otaka A, Yajima H, Takagi H (1987) Calcitonin gene-related peptide promotes mechanical nociception by potentiating release of substance P from the spinal dorsal horn in rats. Brain Res 403:350–354

    CAS  PubMed  Google Scholar 

  • Old EA, Malcangio M (2012) Chemokine mediated neuron-glia communication and aberrant signalling in neuropathic pain states. Curr Opin Pharmacol 12:67–73

    CAS  PubMed  Google Scholar 

  • Olechowski CJ, Truong JJ, Kerr BJ (2009) Neuropathic pain behaviours in a chronic-relapsing model of experimental autoimmune encephalomyelitis (EAE). Pain 141:156–164

    CAS  PubMed  Google Scholar 

  • Pan Y, Lloyd C, Zhou H, Dolich S, Deeds J, Gonzalo JA, Vath J, Gosselin M, Ma J, Dussault B, Woolf E, Alperin G, Culpepper J, Gutierrez-Ramos JC, Gearing D (1997) Neurotactin, a membrane-anchored chemokine upregulated in brain inflammation. Nature 387:611–617

    CAS  PubMed  Google Scholar 

  • Paolicelli RC, Bolasco G, Pagani F, Maggi L, Scianni M, Panzanelli P, Giustetto M, Ferreira TA, Guiducci E, Dumas L, Ragozzino D, Gross CT (2011) Synaptic pruning by microglia is necessary for normal brain development. Science 333:1456–1458

    CAS  PubMed  Google Scholar 

  • Park CK, Lu N, Xu ZZ, Liu T, Serhan CN, Ji RR (2011) Resolving TRPV1- and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci 31:15072–15085

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427–434

    PubMed  Google Scholar 

  • Perry VH, Hume DA, Gordon S (1985) Immunohistochemical localization of macrophages and microglia in the adult and developing mouse brain. Neuroscience 15:313–326

    CAS  PubMed  Google Scholar 

  • Peters CM, Jimenez-Andrade JM, Kuskowski MA, Ghilardi JR, Mantyh PW (2007) An evolving cellular pathology occurs in dorsal root ganglia, peripheral nerve and spinal cord following intravenous administration of paclitaxel in the rat. Brain Res 1168:46–59

    PubMed Central  CAS  PubMed  Google Scholar 

  • Pezet S, Malcangio M, Lever IJ, Perkinton MS, Thompson SW, Williams RJ, McMahon SB (2002) Noxious stimulation induces Trk receptor and downstream ERK phosphorylation in spinal dorsal horn. Mol Cell Neurosci 21:684–695

    CAS  PubMed  Google Scholar 

  • Porter JT, McCarthy KD (1997) Astrocytic neurotransmitter receptors in situ and in vivo. Prog Neurobiol 51:439–455

    CAS  PubMed  Google Scholar 

  • Prinz M, Mildner A (2011) Microglia in the CNS: immigrants from another world. Glia 59:177–187

    PubMed  Google Scholar 

  • Raghavendra V, Tanga FY, DeLeo JA (2004) Complete Freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur J Neurosci 20:467–473

    PubMed  Google Scholar 

  • Ransohoff RM, Cardona AE (2010) The myeloid cells of the central nervous system parenchyma. Nature 468:253–262

    CAS  PubMed  Google Scholar 

  • Ransohoff RM, Perry VH (2009) Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 27:119–145

    CAS  PubMed  Google Scholar 

  • Rasley A, Bost KL, Olson JK, Miller SD, Marriott I (2002) Expression of functional NK-1 receptors in murine microglia. Glia 37:258–267

    PubMed  Google Scholar 

  • Reeve AJ, Patel S, Fox A, Walker K, Urban L (2000) Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur J Pain 4:247–257

    CAS  PubMed  Google Scholar 

  • Ren K, Torres R (2009) Role of interleukin-1beta during pain and inflammation. Brain Res Rev 60:57–64

    PubMed Central  CAS  PubMed  Google Scholar 

  • Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20:570–577

    CAS  PubMed  Google Scholar 

  • Romero-Sandoval A, Chai N, Nutile-McMenemy N, DeLeo JA (2008) A comparison of spinal Iba1 and GFAP expression in rodent models of acute and chronic pain. Brain Res 1219:116–126

    PubMed Central  CAS  PubMed  Google Scholar 

  • Rubartelli A, Cozzolino F, Talio M, Sitia R (1990) A novel secretory pathway for interleukin-1 beta, a protein lacking a signal sequence. EMBO J 9:1503–1510

    PubMed Central  CAS  PubMed  Google Scholar 

  • Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787

    CAS  PubMed  Google Scholar 

  • Salter MW, Beggs S (2014) Sublime microglia: expanding roles for the guardians of the CNS. Cell 158:15–24

    CAS  PubMed  Google Scholar 

  • Sandkuhler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758

    PubMed  Google Scholar 

  • Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, Ransohoff RM, Greenberg ME, Barres BA, Stevens B (2012) Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner. Neuron 74:691–705

    PubMed Central  CAS  PubMed  Google Scholar 

  • Schafers M, Svensson CI, Sommer C, Sorkin LS (2003) Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 23:2517–2521

    CAS  PubMed  Google Scholar 

  • Schaible HG, Richter F, Ebersberger A, Boettger MK, Vanegas H, Natura G, Vazquez E, von Segond BG (2009) Joint pain. Exp Brain Res 196:153–162

    PubMed  Google Scholar 

  • Schroder K, Tschopp J (2010) The inflammasomes. Cell 140:821–832

    CAS  PubMed  Google Scholar 

  • Sedel F, Bechade C, Vyas S, Triller A (2004) Macrophage-derived tumor necrosis factor alpha, an early developmental signal for motoneuron death. J Neurosci 24:2236–2246

    CAS  PubMed  Google Scholar 

  • Seybold VS, McCarson KE, Mermelstein PG, Groth RD, Abrahams LG (2003) Calcitonin gene-related peptide regulates expression of neurokinin1 receptors by rat spinal neurons. J Neurosci 23:1816–1824

    CAS  PubMed  Google Scholar 

  • Shubayev VI, Myers RR (2000) Upregulation and interaction of TNFalpha and gelatinases A and B in painful peripheral nerve injury. Brain Res 855:83–89

    CAS  PubMed  Google Scholar 

  • Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35

    PubMed Central  PubMed  Google Scholar 

  • Sokka T, Kautiainen H, Toloza S, Makinen H, Verstappen SM, Lund HM, Naranjo A, Baecklund E, Herborn G, Rau R, Cazzato M, Gossec L, Skakic V, Gogus F, Sierakowski S, Bresnihan B, Taylor P, McClinton C, Pincus T (2007) QUEST-RA: quantitative clinical assessment of patients with rheumatoid arthritis seen in standard rheumatology care in 15 countries. Ann Rheum Dis 66:1491–1496

    PubMed Central  PubMed  Google Scholar 

  • Sommer C, Kress M (2004) Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosci Lett 361:184–187

    CAS  PubMed  Google Scholar 

  • Sommer C, Schafers M (1998) Painful mononeuropathy in C57BL/Wld mice with delayed Wallerian degeneration: differential effects of cytokine production and nerve regeneration on thermal and mechanical hypersensitivity. Brain Res 784:154–162

    CAS  PubMed  Google Scholar 

  • Staniland AA, Clark AK, Wodarski R, Sasso O, Maione F, D’Acquisto F, Malcangio M (2010) Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. J Neurochem 114:1143–1157

    CAS  PubMed  Google Scholar 

  • Steinhauser C, Berger T, Frotscher M, Kettenmann H (1992) Heterogeneity in the membrane current pattern of identified glial cells in the hippocampal slice. Eur J Neurosci 4:472–484

    PubMed  Google Scholar 

  • Stevens B, Allen NJ, Vazquez LE, Howell GR, Christopherson KS, Nouri N, Micheva KD, Mehalow AK, Huberman AD, Stafford B, Sher A, Litke AM, Lambris JD, Smith SJ, John SW, Barres BA (2007) The classical complement cascade mediates CNS synapse elimination. Cell 131:1164–1178

    CAS  PubMed  Google Scholar 

  • Sung CS, Wen ZH, Chang WK, Ho ST, Tsai SK, Chang YC, Wong CS (2004) Intrathecal interleukin-1beta administration induces thermal hyperalgesia by activating inducible nitric oxide synthase expression in the rat spinal cord. Brain Res 1015:145–153

    CAS  PubMed  Google Scholar 

  • Suter MR, Berta T, Gao YJ, Decosterd I, Ji RR (2009) Large A-fiber activity is required for microglial proliferation and p38 MAPK activation in the spinal cord: different effects of resiniferatoxin and bupivacaine on spinal microglial changes after spared nerve injury. Mol Pain 5:53

    PubMed Central  PubMed  Google Scholar 

  • Suzuki T, Hide I, Ido K, Kohsaka S, Inoue K, Nakata Y (2004) Production and release of neuroprotective tumor necrosis factor by P2X7 receptor-activated microglia. J Neurosci 24:1–7

    CAS  PubMed  Google Scholar 

  • Svensson CI, Hua XY, Protter AA, Powell HC, Yaksh TL (2003a) Spinal p38 MAP kinase is necessary for NMDA-induced spinal PGE(2) release and thermal hyperalgesia. Neuroreport 14:1153–1157

    CAS  PubMed  Google Scholar 

  • Svensson CI, Marsala M, Westerlund A, Calcutt NA, Campana WM, Freshwater JD, Catalano R, Feng Y, Protter AA, Scott B, Yaksh TL (2003b) Activation of p38 mitogen-activated protein kinase in spinal microglia is a critical link in inflammation-induced spinal pain processing. J Neurochem 86:1534–1544

    CAS  PubMed  Google Scholar 

  • Svensson CI, Fitzsimmons B, Azizi S, Powell HC, Hua XY, Yaksh TL (2005a) Spinal p38beta isoform mediates tissue injury-induced hyperalgesia and spinal sensitization. J Neurochem 92:1508–1520

    CAS  PubMed  Google Scholar 

  • Svensson CI, Schafers M, Jones TL, Powell H, Sorkin LS (2005b) Spinal blockade of TNF blocks spinal nerve ligation-induced increases in spinal P-p38. Neurosci Lett 379:209–213

    CAS  PubMed  Google Scholar 

  • Sweitzer SM, Colburn RW, Rutkowski M, DeLeo JA (1999) Acute peripheral inflammation induces moderate glial activation and spinal IL-1beta expression that correlates with pain behavior in the rat. Brain Res 829:209–221

    CAS  PubMed  Google Scholar 

  • Tanga FY, Raghavendra V, DeLeo JA (2004) Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 45:397–407

    CAS  PubMed  Google Scholar 

  • Tarozzo G, Bortolazzi S, Crochemore C, Chen SC, Lira AS, Abrams JS, Beltramo M (2003) Fractalkine protein localization and gene expression in mouse brain. J Neurosci Res 73:81–88

    CAS  PubMed  Google Scholar 

  • Tawfik VL, Nutile-McMenemy N, Lacroix-Fralish ML, DeLeo JA (2007) Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury. Brain Behav Immun 21:238–246

    CAS  PubMed  Google Scholar 

  • Todd AJ (2010) Neuronal circuitry for pain processing in the dorsal horn. Nat Rev Neurosci 11:823–836

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tong N, Perry SW, Zhang Q, James HJ, Guo H, Brooks A, Bal H, Kinnear SA, Fine S, Epstein LG, Dairaghi D, Schall TJ, Gendelman HE, Dewhurst S, Sharer LR, Gelbard HA (2000) Neuronal fractalkine expression in HIV-1 encephalitis: roles for macrophage recruitment and neuroprotection in the central nervous system. J Immunol 164:1333–1339

    CAS  PubMed  Google Scholar 

  • Trang T, Beggs S, Wan X, Salter MW (2009) P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. J Neurosci 29:3518–3528

    PubMed Central  CAS  PubMed  Google Scholar 

  • Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527

    PubMed Central  PubMed  Google Scholar 

  • Trentham DE (1982) Collagen arthritis as a relevant model for rheumatoid arthritis. Arthritis Rheum 25:911–916

    CAS  PubMed  Google Scholar 

  • Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, Inoue K (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424:778–783

    CAS  PubMed  Google Scholar 

  • Tsuda M, Tozaki-Saitoh H, Inoue K (2012) Purinergic system, microglia and neuropathic pain. Curr Opin Pharmacol 12:74–79

    CAS  PubMed  Google Scholar 

  • Vazquez E, Kahlenbach J, von Segond BG, Konig C, Schaible HG, Ebersberger A (2012) Spinal interleukin-6 is an amplifier of arthritic pain in the rat. Arthritis Rheum 64:2233–2242

    CAS  PubMed  Google Scholar 

  • Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC (2004) Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 20:1150–1160

    PubMed  Google Scholar 

  • Verpoorten N, Claeys KG, Deprez L, Jacobs A, Van Gerwen V, Lagae L, Arts WF, De Meirleir L, Keymolen K, Ceuterick-de GC, De Jonghe P, Timmerman V, Nelis E (2006) Novel frameshift and splice site mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) associated with hereditary sensory neuropathy type IV. Neuromuscul Disord 16:19–25

    PubMed  Google Scholar 

  • Vincent TL, Williams RO, Maciewicz R, Silman A, Garside P (2012) Mapping pathogenesis of arthritis through small animal models. Rheumatology (Oxford) 51:1931–1941

    Google Scholar 

  • Viviani B, Bartesaghi S, Gardoni F, Vezzani A, Behrens MM, Bartfai T, Binaglia M, Corsini E, Di LM, Galli CL, Marinovich M (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J Neurosci 23:8692–8700

    CAS  PubMed  Google Scholar 

  • Volterra A, Meldolesi J (2005) Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci 6:626–640

    CAS  PubMed  Google Scholar 

  • Walsh DA, McWilliams DF (2014) Mechanisms, impact and management of pain in rheumatoid arthritis. Nat Rev Rheumatol 10(10):581–592

    CAS  PubMed  Google Scholar 

  • Wang DD, Bordey A (2008) The astrocyte odyssey. Prog Neurobiol 86:342–367

    PubMed Central  CAS  PubMed  Google Scholar 

  • Watkins LR, Martin D, Ulrich P, Tracey KJ, Maier SF (1997) Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71:225–235

    CAS  PubMed  Google Scholar 

  • Weber A, Wasiliew P, Kracht M (2010) Interleukin-1 (IL-1) pathway. Sci Signal 3:cm1

    PubMed  Google Scholar 

  • Wen YR, Suter MR, Kawasaki Y, Huang J, Pertin M, Kohno T, Berde CB, Decosterd I, Ji RR (2007) Nerve conduction blockade in the sciatic nerve prevents but does not reverse the activation of p38 mitogen-activated protein kinase in spinal microglia in the rat spared nerve injury model. Anesthesiology 107:312–321

    PubMed  Google Scholar 

  • Weng HR, Chen JH, Cata JP (2006) Inhibition of glutamate uptake in the spinal cord induces hyperalgesia and increased responses of spinal dorsal horn neurons to peripheral afferent stimulation. Neuroscience 138:1351–1360

    CAS  PubMed  Google Scholar 

  • Williams RO (1998) Rodent models of arthritis: relevance for human disease. Clin Exp Immunol 114:330–332

    PubMed Central  CAS  PubMed  Google Scholar 

  • Williams RO (2004) Collagen-induced arthritis as a model for rheumatoid arthritis. Methods Mol Med 98:207–216

    CAS  PubMed  Google Scholar 

  • Wolf G, Gabay E, Tal M, Yirmiya R, Shavit Y (2006) Genetic impairment of interleukin-1 signaling attenuates neuropathic pain, autotomy, and spontaneous ectopic neuronal activity, following nerve injury in mice. Pain 120:315–324

    CAS  PubMed  Google Scholar 

  • Woolf CJ, Mannion RJ (1999) Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 353:1959–1964

    CAS  PubMed  Google Scholar 

  • Youn DH, Wang H, Jeong SJ (2008) Exogenous tumor necrosis factor-alpha rapidly alters synaptic and sensory transmission in the adult rat spinal cord dorsal horn. J Neurosci Res 86:2867–2875

    CAS  PubMed  Google Scholar 

  • Zhang J, Shi XQ, Echeverry S, Mogil JS, De KY, Rivest S (2007) Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci 27:12396–12406

    CAS  PubMed  Google Scholar 

  • Zhang RX, Li A, Liu B, Wang L, Ren K, Zhang H, Berman BM, Lao L (2008) IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain 135:232–239

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhang L, Berta T, Xu ZZ, Liu T, Park JY, Ji RR (2011) TNF-alpha contributes to spinal cord synaptic plasticity and inflammatory pain: distinct role of TNF receptor subtypes 1 and 2. Pain 152:419–427

    PubMed Central  CAS  PubMed  Google Scholar 

  • Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, Decosterd I, Ji RR (2006) A peptide c-Jun N-terminal kinase (JNK) inhibitor blocks mechanical allodynia after spinal nerve ligation: respective roles of JNK activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26:3551–3560

    CAS  PubMed  Google Scholar 

  • Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR (2007) 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 21:642–651

    PubMed Central  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marzia Malcangio .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer-Verlag Berlin Heidelberg

About this chapter

Cite this chapter

Old, E.A., Clark, A.K., Malcangio, M. (2015). The Role of Glia in the Spinal Cord in Neuropathic and Inflammatory Pain. In: Schaible, HG. (eds) Pain Control. Handbook of Experimental Pharmacology, vol 227. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-46450-2_8

Download citation

Publish with us

Policies and ethics