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http://dx.doi.org/10.3344/kjp.2009.22.1.1

Glial Mechanisms of Neuropathic Pain and Emerging Interventions  

Jo, Daehyun (Pain Research Center, Department of Anesthesiology, School of Medicine, University of Utah)
Chapman, C. Richard (Pain Research Center, Department of Anesthesiology, School of Medicine, University of Utah)
Light, Alan R. (Pain Research Center, Department of Anesthesiology, School of Medicine, University of Utah)
Publication Information
The Korean Journal of Pain / v.22, no.1, 2009 , pp. 1-15 More about this Journal
Abstract
Neuropathic pain is often refractory to intervention because of the complex etiology and an incomplete understanding of the mechanisms behind this type of pain. Glial cells, specifically microglia and astrocytes, are powerful modulators of pain and new targets of drug development for neuropathic pain. Glial activation could be the driving force behind chronic pain, maintaining the noxious signal transmission even after the original injury has healed. Glia express chemokine, purinergic, toll-like, glutaminergic and other receptors that enable them to respond to neural signals, and they can modulate neuronal synaptic function and neuronal excitability. Nerve injury upregulates multiple receptors in spinal microglia and astrocytes. Microglia influence neuronal communication by producing inflammatory products at the synapse, as do astrocytes because they completely encapsulate synapses and are in close contact with neuronal somas through gap junctions. Glia are the main source of inflammatory mediators in the central nervous system. New therapeutic strategies for neuropathic pain are emerging such as targeting the glial cells, novel pharmacologic approaches and gene therapy. Drugs targeting microglia and astrocytes, cytokine production, and neural structures including dorsal root ganglion are now under study, as is gene therapy. Isoform-specific inhibition will minimize the side effects produced by blocking all glia with a general inhibitor. Enhancing the anti-inflammatory cytokines could prove more beneficial than administering proinflammatory cytokine antagonists that block glial activation systemically. Research on therapeutic gene transfer to the central nervous system is underway, although obstacles prevent immediate clinical application.
Keywords
astrocytes; mechanisms; microglia; neuropathic pain; therapeutic strategies;
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1 Dworkin RH, Portenoy RK: Pain and its persistence in herpes zoster. Pain 1996;67: 241-51   DOI   PUBMED   ScienceOn
2 Tsuda M, Inoue K, Salter MW: Neuropathic pain and spinal microglia: a big problem from molecules in 'small' glia. Trends Neurosci 2005; 28: 101-7   DOI   ScienceOn
3 Light AR, Wu Y, Hughen RW, Guthrie PB: Purinergic receptors activating rapid intracellular Ca increases in microglia. Neuron Glia Biol 2006; 2: 125-38   DOI   ScienceOn
4 Kumar S, Boehm J, Lee JC: p38 MAP kinases: key signalling molecules as therapeutic targets for inflammatory diseases. Nat Rev Drug Discov 2003; 2: 717-26   DOI   ScienceOn
5 Jana M, Dasgupta S, Saha RN, Liu X, Pahan K: Induction of tumor necrosis factor-alpha (TNF-alpha) by interleukin-12 p40 monomer and homodimer in microglia and macrophages. J Neurochem 2003; 86: 519-28   DOI   ScienceOn
6 Krakauer T: Molecular therapeutic targets in inflammation:cyclooxygenase and NF-kappaB. Curr Drug Targets Inflamm Allergy 2004; 3: 317-24   DOI   ScienceOn
7 Haynes SE, Hollopeter G, Yang G, Kurpius D, Dailey ME, Gan WB, et al: The P2Y12 receptor regulates microglial activation by extracellular nucleotides. Nat Neurosci 2006;9: 1512-9   DOI   ScienceOn
8 Zhuang ZY, Gerner P, Woolf CJ, Ji RR: ERK is sequentially activated in neurons, microglia, and astrocytes by spinal nerve ligation and contributes to mechanical allodynia in this neuropathic pain model. Pain 2005; 114: 149-59   DOI   ScienceOn
9 Rebenko-Moll NM, Liu L, Cardona A, Ransohoff RM:Chemokines, mononuclear cells and the nervous system:heaven (or hell) is in the details. Curr Opin Immunol 2006;18: 683-9   DOI   ScienceOn
10 Jung H, Toth PT, White FA, Miller RJ: Monocyte chemoattractant protein-1 functions as a neuromodulator in dorsal root ganglia neurons. J Neurochem 2008; 104: 254-63   PUBMED   ScienceOn
11 Gay NJ, Gangloff M: Structure and function of Toll receptors and their ligands. Annu Rev Biochem 2007; 76:141-65   DOI   ScienceOn
12 Hutchinson MR, Zhang Y, Brown K, Coats BD, Shridhar M, Sholar PW, et al: Non-stereoselective reversal of neuropathic pain by naloxone and naltrexone: involvement of toll-like receptor 4 (TLR4). Eur J Neurosci 2008; 28: 20-9   DOI   ScienceOn
13 Garrison CJ, Dougherty PM, Kajander KC, Carlton SM:Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res 1991; 565: 1-7   DOI   ScienceOn
14 Peters CM, Rogers SD, Pomonis JD, Egnaczyk GF, Keyser CP, Schmidt JA, et al: Endothelin receptor expression in the normal and injured spinal cord: potential involvement in injury-induced ischemia and gliosis. Exp Neurol 2003;180:1-13   DOI   ScienceOn
15 Eclancher F, Perraud F, Faltin J, Labourdette G, Sensenbrenner M: Reactive astrogliosis after basic fibroblast growth factor (bFGF) injection in injured neonatal rat brain. Glia 1990; 3: 502-9   DOI   PUBMED
16 Milligan ED, Twining C, Chacur M, Biedenkapp J, O'Connor K, Poole S, et al: Spinal glia and proinflammatory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci 2003; 23: 1026-40   ScienceOn
17 Aumeerally N, Allen G, Sawynok J: Glutamate-evoked release of adenosine and regulation of peripheral nociception. Neuroscience 2004; 127: 1-11   DOI   ScienceOn
18 Zhang SC, Goetz BD, Duncan ID: Suppression of activated microglia promotes survival and function of transplanted oligodendroglial progenitors. Glia 2003; 41: 191-8   DOI   ScienceOn
19 Sch$\ddot{a}$fers M, Svensson CI, Sommer C, Sorkin LS: Tumor necrosis factor-alpha induces mechanical allodynia after spinal nerve ligation by activation of p38 MAPK in primary sensory neurons. J Neurosci 2003; 23: 2517-21   ScienceOn
20 Ji RR, Suter MR: p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain 2007; 3: 33   DOI   ScienceOn
21 Pires MM, Emmert D, Hrycyna CA, Chmielewski J: Inhibition of P-glycoprotein-mediated paclitaxel resistance by reversibly linked quinine homodimers. Mol Pharmacol 2009; 75: 92-100   DOI   ScienceOn
22 Beltramo M, Bernardini N, Bertorelli R, Campanella M, Nicolussi E, Fredduzzi S, et al: CB2 receptor- mediated antihyperalgesia: possible direct involvement of neural mechanisms. Eur J Neurosci 2006; 23: 1530-8   DOI   ScienceOn
23 Ji RR, Baba H, Brenner GJ, Woolf CJ: Nociceptive-specific activation of ERK in spinal neurons contributes to pain hypersensitivity. Nat Neurosci 1999; 2: 1114-9   DOI   ScienceOn
24 White FA, Sun J, Waters SM, Ma C, Ren D, Ripsch M, et al: Excitatory monocyte chemoattractant protein-1 signaling is up-regulated in sensory neurons after chronic compression of the dorsal root ganglion. Proc Natl Acad Sci USA 2005; 102: 14092-7   DOI   ScienceOn
25 Bhat NR, Zhang P, Lee JC, Hogan EL: Extracellular signal-regulated kinase and p38 subgroups of mitogenactivated protein kinases regulate inducible nitric oxide synthase and tumor necrosis factor-alpha gene expression in endotoxin-stimulated primary glial cultures. J Neurosci 1998; 18: 1633-41   ScienceOn
26 Gunnarsson I, Nordmark B, Hassan Bakri A, Gröndal G, Larsson P, Forslid J, et al: Development of lupus-related side-effects in patients with early RA during sulphasalazine treatment-the role of IL-10 and HLA. Rheumatology (Oxford) 2000; 39: 886-93   DOI   ScienceOn
27 Tan PH, Janes SE, Handa AI, Friend PJ: More trouble ahead; is gene therapy coming of age? Expert Opin Biol Ther 2008; 8: 561-7   DOI   ScienceOn
28 Gehrmann J, Matsumoto Y, Kreutzberg GW: Microglia:intrinsic immuneffector cell of the brain. Brain Res Brain Res Rev 1995; 20: 269-87   DOI   PUBMED   ScienceOn
29 Raouf R, Chabot-Dor$\grave{e}$ AJ, Ase AR, Blais D, S$\grave{e}$gu$\grave{e}$la P: Differential regulation of microglial P2X4 and P2X7 ATP receptors following LPS-induced activation. Neuropharmacology 2007; 53: 496-504   DOI   ScienceOn
30 Zhang J, De Koninck Y: Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 2006; 97: 772-83   DOI   ScienceOn
31 Ferrara N, Ousley F, Gospodarowicz D: Bovine brain astrocytes express basic fibroblast growth factor, a neurotropic and angiogenic mitogen. Brain Res 1988; 462:223-32   DOI   ScienceOn
32 Ji RR, Befort K, Brenner GJ, Woolf CJ: ERK MAP kinase activation in superficial spinal cord neurons induces prodynorphin and NK-1 upregulation and contributes to persistent inflammatory pain hypersensitivity. J Neurosci 2002;22: 478-85   ScienceOn
33 Goss JR, Goins WF, Glorioso JC: Gene therapy applications for the treatment of neuropathic pain. Expert Rev Neurother 2007; 7: 487-506   DOI   ScienceOn
34 Rogers SD, Peters CM, Pomonis JD, Hagiwara H, Ghilardi JR, Mantyh PW: Endothelin B receptors are expressed by astrocytes and regulate astrocyte hypertrophy in the normal and injured CNS. Glia 2003; 41: 180-90   DOI   ScienceOn
35 Margolles-Clark E, Jacques-Silva MC, Ganesan L, Umland O, Kenyon NS, Ricordi C, et al: Suramin inhibits the CD40-CD154 costimulatory interaction: a possible mechanism for immunosuppressive effects. Biochem Pharmacol 2009; 77: 1236-45   DOI   ScienceOn
36 Wieseler-Frank J, Maier SF, Watkins LR: Glial activation and pathological pain. Neurochem Int 2004; 45: 389-95   DOI   ScienceOn
37 Spataro LE, Sloane EM, Milligan ED, Wieseler-Frank J, Schoeniger D, Jekich BM, et al: Spinal gap junctions:potential involvement in pain facilitation. J Pain 2004; 5:392-405   DOI   ScienceOn
38 Tsuda M, Shigemoto-Mogami Y, Koizumi S, Mizokoshi A, Kohsaka S, Salter MW, et al: P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 2003; 424: 778-83   DOI   ScienceOn
39 Madiai F, Goettl VM, Hussain SR, Clairmont AR, Stephens RL Jr, Hackshaw KV: Anti-fibroblast growth factor-2 antibodies attenuate mechanical allodynia in a rat model of neuropathic pain. J Mol Neurosci 2005; 27: 315-24   DOI   ScienceOn
40 Wen YR, Suter MR, Kawasaki Y, Huang J, Pertin M, Kohno T, et al: 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 2007; 107:312-21   DOI   ScienceOn
41 Ledeboer A, Sloane EM, Milligan ED, Frank MG, Mahony JH, Maier SF, et al: Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 2005; 115: 71-83   DOI   PUBMED   ScienceOn
42 Hucho T, Levine JD: Signaling pathways in sensitization:toward a nociceptor cell biology. Neuron 2007; 55: 365-76   DOI   ScienceOn
43 Tozaki-Saitoh H, Tsuda M, Miyata H, Ueda K, Kohsaka S, Inoue K: P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. J Neurosci 2008; 28: 4949-56   DOI   ScienceOn
44 Tanga FY, Nutile-McMenemy N, DeLeo JA: The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 2005; 102: 5856-61   DOI   ScienceOn
45 Romero-Sandoval EA, Horvath RJ, DeLeo JA: Neuroimmune interactions and pain: focus on glial-modulating targets. Curr Opin Investig Drugs 2008; 9: 726-34   ScienceOn
46 Milligan ED, Soderquist RG, Malone SM, Mahoney JH, Hughes TS, Langer SJ, et al: Intrathecal polymer-based interleukin-10 gene delivery for neuropathic pain. Neuron Glia Biol 2006; 2: 293-308   DOI   ScienceOn
47 Watkins LR, Maier SF: Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov 2003; 2: 973-85   DOI   ScienceOn
48 Zhang FY, Wan Y, Zhang ZK, Light AR, Fu KY: Peripheral formalin injection induces long-lasting increases in cyclooxygenase 1 expression by microglia in the spinal cord. J Pain 2007; 8: 110-7   DOI   ScienceOn
49 Campbell JN, Meyer RA: Mechanisms of neuropathic pain. Neuron 2006; 52: 77-92   DOI   ScienceOn
50 Bettoni I, Comelli F, Rossini C, Granucci F, Giagnoni G, Peri F, et al: Glial TLR4 receptor as new target to treat neuropathic pain: efficacy of a new receptor antagonist in a model of peripheral nerve injury in mice. Glia 2008; 56:1312-9   DOI   ScienceOn
51 Vitkovic L, Bockaert J, Jacque C: "Inflammatory" cytokines: neuromodulators in normal brain? J Neurochem 2000; 74: 457-71   DOI   ScienceOn
52 Kim D, Kim MA, Cho IH, Kim MS, Lee S, Jo EK, et al:A critical role of toll-like receptor 2 in nerve injury-induced spinal cord glial cell activation and pain hypersensitivity. J Biol Chem 2007; 282: 14975-83   DOI   ScienceOn
53 Padi SS, Kulkarni SK: Minocycline prevents the development of neuropathic pain, but not acute pain: possible anti-inflammatory and antioxidant mechanisms. Eur J Pharmacol 2008; 601: 79-87   DOI   PUBMED   ScienceOn
54 Hanisch UK: Microglia as a source and target of cytokines. Glia 2002; 40: 140-55   DOI   PUBMED   ScienceOn
55 Ji RR, Kawasaki Y, Zhuang ZY, Wen YR, Zhang YQ: Protein kinases as potential targets for the treatment of pathological pain. Handb Exp Pharmacol 2007; 177: 359-89   DOI   PUBMED   ScienceOn
56 Rabchevsky AG, Fugaccia I, Turner AF, Blades DA, Mattson MP, Scheff SW: Basic fibroblast growth factor (bFGF) enhances functional recovery following severe spinal cord injury to the rat. Exp Neurol 2000; 164: 280-91   DOI   ScienceOn
57 McCleane G: Pharmacological management of neuropathic pain. CNS Drugs 2003; 17: 1031-43   DOI   PUBMED   ScienceOn
58 Colburn RW, DeLeo JA, Rickman AJ, Yeager MP, Kwon P, Hickey WF: Dissociation of microglial activation and neuropathic pain behaviors following peripheral nerve injury in the rat. J Neuroimmunol 1997; 79: 163-75   DOI   ScienceOn
59 Mata M, Hao S, Fink DJ: Gene therapy directed at the neuroimmune component of chronic pain with particular attention to the role of TNF alpha. Neurosci Lett 2008; 437:209-13   DOI   ScienceOn
60 Jolivalt CG, Lee CA, Ramos KM, Calcutt NA: Allodynia and hyperalgesia in diabetic rats are mediated by GABA and depletion of spinal potassium-chloride co-transporters. Pain 2008; 140: 48-57   DOI   ScienceOn
61 Lee TT, Green BA, Dietrich WD, Yezierski RP: Neuroprotective effects of basic fibroblast growth factor following spinal cord contusion injury in the rat. J Neurotrauma 1999;16: 347-56   DOI   PUBMED
62 Tawfik VL, Nutile-McMenemy N, Lacroix-Fralish ML, Deleo JA: Efficacy of propentofylline, a glial modulating agent, on existing mechanical allodynia following peripheral nerve injury. Brain Behav Immun 2007; 21: 238-46   DOI   ScienceOn
63 Falsig J, P$\ddot{o}$rzgen P, Lotharius J, Leist M: Specific modulation of astrocyte inflammation by inhibition of mixed lineage kinases with CEP-1347. J Immunol 2004; 173:2762-70   ScienceOn
64 Mika J: Modulation of microglia can attenuate neuropathic pain symptoms and enhance morphine effectiveness. Pharmacol Rep 2008; 60: 297-307   PUBMED   ScienceOn
65 Abbadie C, Lindia JA, Cumiskey AM, Peterson LB, Mudgett JS, Bayne EK, et al: Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci USA 2003; 100: 7947-52   DOI   ScienceOn
66 Miyake K: Innate immune sensing of pathogens and danger signals by cell surface Toll-like receptors. Semin Immunol 2007; 19: 3-10   DOI   PUBMED   ScienceOn
67 Koshinaga M, Sanon HR, Whittemore SR: Altered acidic and basic fibroblast growth factor expression following spinal cord injury. Exp Neurol 1993; 120: 32-48   DOI   ScienceOn
68 Borsello T, Bonny C: Use of cell-permeable peptides to prevent neuronal degeneration. Trends Mol Med 2004; 10:239-44   DOI   ScienceOn
69 Khasar SG, McCarter G, Levine JD: Epinephrine produces a beta-adrenergic receptor-mediated mechanical hyperalgesia and in vitro sensitization of rat nociceptors. J Neurophysiol 1999; 81: 1104-12   DOI   PUBMED   ScienceOn
70 Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K:Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci 2008; 28: 12775-87   DOI   ScienceOn
71 Zhuang ZY, Kawasaki Y, Tan PH, Wen YR, Huang J, Ji RR: 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; 21: 642-51   DOI   ScienceOn
72 Si J, Fu X, Behar J, Wands J, Beer DG, Souza RF, et al:NADPH oxidase NOX5-S mediates acid-induced cyclooxygenase-2 expression via activation of NF-kappaB in Barrett's esophageal adenocarcinoma cells. J Biol Chem 2007;282: 16244-55   DOI   ScienceOn
73 Thacker MA, Clark AK, Bishop T, Grist J, Yip PK, Moon LD, et al: CCL2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 2009; 13: 263-72   DOI   ScienceOn
74 Zhuang ZY, Wen YR, Zhang DR, Borsello T, Bonny C, Strichartz GR, et al: 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 2006; 26:3551-60   DOI   ScienceOn
75 Yarowsky P, Boyne AF, Wierwille R, Brookes N: Effect of monensin on deoxyglucose uptake in cultured astrocytes:energy metabolism is coupled to sodium entry. J Neurosci 1986; 6: 859-66
76 Raghavendra V, Tanga F, DeLeo JA: Inhibition of microglial activation attenuates the development but not existing hypersensitivity in a rat model of neuropathy. J Pharmacol Exp Ther 2003; 306: 624-30   DOI   ScienceOn
77 Verge GM, Milligan ED, Maier SF, Watkins LR, Naeve GS, Foster AC: Fractalkine (CX3CL1) and fractalkine receptor (CX3CR1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 2004; 20: 1150-60   DOI   ScienceOn
78 Borsello T, Clarke PG, Hirt L, Vercelli A, Repici M, Schorderet DF, et al: A peptide inhibitor of c-Jun Nterminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 2003; 9: 1180-6   DOI   ScienceOn
79 Ashton JC, Glass M: The cannabinoid CB2 receptor as a target for inflammation-dependent neurodegeneration. Curr Neuropharmacol 2007; 5: 73-80   DOI   ScienceOn
80 Woolf CJ, Mannion RJ: Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999; 353:1959-64   DOI   ScienceOn
81 Hassel B, Paulsen RE, Johnsen A, Fonnum F: Selective inhibition of glial cell metabolism in vivo by fluorocitrate. Brain Res 1992; 576: 120-4   DOI   ScienceOn
82 Dansereau MA, Gosselin RD, Pohl M, Pommier B, Mechighel P, Mauborgne A, et al: Spinal CCL2 pronociceptive action is no longer effective in CCR2 receptor antagonist-treated rats. J Neurochem 2008; 106: 757-69   DOI   ScienceOn
83 Takano T, Tian GF, Peng W, Lou N, Libionka W, Han X, et al: Astrocyte-mediated control of cerebral blood flow. Nat Neurosci 2006; 9: 260-7   DOI   ScienceOn
84 Hutchinson MR, Lewis SS, Coats BD, Skyba DA, Crysdale NY, Berkelhammer DL, et al: Reduction of opioid withdrawal and potentiation of acute opioid analgesia by systemic AV411 (ibudilast). Brain Behav Immun 2009; 23:240-50   DOI   ScienceOn
85 Wei F, Zhuo M: Activation of Erk in the anterior cingulate cortex during the induction and expression of chronic pain. Mol Pain 2008; 4: 28   DOI   ScienceOn
86 Meller ST, Dykstra C, Grzybycki D, Murphy S, Gebhart GF: The possible role of glia in nociceptive processing and hyperalgesia in the spinal cord of the rat. Neuropharmacology 1994; 33: 1471-8   DOI   ScienceOn
87 Sommer C: Painful neuropathies. Curr Opin Neurol 2003;16: 623-8   DOI   PUBMED   ScienceOn
88 Manzanares J, Julian M, Carrascosa A: Role of the cannabinoid system in pain control and therapeutic implications for the management of acute and chronic pain episodes. Curr Neuropharmacol 2006; 4: 239-57   DOI   ScienceOn