Skip to main content Accessibility help
  • Print publication year: 2013
  • Online publication date: December 2013

Chapter 8 - Pathophysiology of neuropathic pain: signaling pathways and their magnification – the role of neuronal Toll-like receptors

from Section 2 - The Condition of Neuropathic Pain


1. WoolfCJ, MannionRJ.Neuropathic pain: aetiology, symptoms, mechanisms, and management. Lancet 1999;353:1959–64.
2. MaC, LaMotteRH.Enhanced excitability of dissociated primary sensory neurons after chronic compression of the dorsal root ganglion in the rat. Pain 2005;113:106–12.
3. MaC, ShuY, ZhengZ, et al. Similar electrophysiological changes in axotomized and neighboring intact dorsal root ganglion neurons. J Neurophysiol 2003;89:1588–602.
4. DevorM.Nerves hurt. Eur J Pain 2009;13:1–2.
5. HouL, WangX.PKC and PKA, but not PKG mediate LPS-induced CGRP release and [Ca(2+)](i) elevation in DRG neurons of neonatal rats. J Neurosci Res 2001;66:592–600.
6. GayNJ, KeithFJ.Drosophila Toll and IL-1 receptor. Nature 1991;351:355–6.
7. SchneiderDS, HudsonKL, LinTY, AndersonKV.Dominant and recessive mutations define functional domains of Toll, a transmembrane protein required for dorsal-ventral polarity in the Drosophila embryo. Genes Dev 1991;5:797–807.
8. OzinskyA, SmithKD, HumeD, UnderhillDM.Co-operative induction of pro-inflammatory signaling by Toll-like receptors. J Endotoxin Res 2000;6:393–6.
9. ReF, StromingerJL.Toll-like receptor 2 (TLR2) and TLR4 differentially activate human dendritic cells. J Biol Chem 2001;276:37692–9.
10. KawaiT, AkiraS.The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010;11:373–84.
11. FitzgeraldKA, Palsson-McDermottEM, BowieAG, et al. Mal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction. Nature 2001;413:78–83.
12. NagaiY, AkashiS, NagafukuM, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol 2002;3:667–72.
13. KawaiT, AkiraS.TLR signaling. Semin Immunol 2007;19:24–32.
14. FerraoR, LiJ, BergaminE, WuH.Structural insights into the assembly of large oligomeric signalosomes in the Toll-like receptor-interleukin-1 receptor superfamily. Sci Signal 2012;5:re3.
15. ApplequistSE, WallinRP, LjunggrenHG.Variable expression of Toll-like receptor in murine innate and adaptive immune cell lines. Int Immunol 2002;14:1065–74.
16. WellsJM, RossiO, MeijerinkM, van BaarlenP.Epithelial crosstalk at the microbiota-mucosal interface. Proc Natl Acad Sci USA 2011;108 Suppl. 1:4607–14.
17. OkunE, GriffioenKJ, MattsonMP.Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci 2011;34:269–81.
18. WadachiR, HargreavesKM.Trigeminal nociceptors express TLR-4 and CD14: a mechanism for pain due to infection. J Dent Res 2006;85:49–53.
19. AcostaC, DaviesA.Bacterial lipopolysaccharide regulates nociceptin expression in sensory neurons. J Neurosci Res 2008;86:1077–86.
20. LiuT, XuZZ, ParkCK, BertaT, JiRR.Toll-like receptor 7 mediates pruritus. Nat Neurosci 2010;13:1460–2.
21. Ochoa-CortesF, Ramos-LomasT, Miranda-MoralesM, et al. Bacterial cell products signal to mouse colonic nociceptive dorsal root ganglia neurons. Am J Physiol Gastrointest Liver Physiol 2010;299:G723–32.
22. DiogenesA, FerrazCC, AkopianAN, HenryMA, HargreavesKM.LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res 2011;90:759–64.
23. DueMR, PiekarzAD, WilsonN, et al. Neuroexcitatory effects of morphine-3-glucuronide are dependent on Toll-like receptor 4 signaling. J Neuroinflammation 2012;9:200.
24. QiJ, BuzasK, FanH, CohenJI, et al. Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol 2011;186:6417–26.
25. AnderssonU, TraceyKJ.HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol 2011;29:139–62.
26. JinMS, LeeJO.Structures of the Toll-like receptor family and its ligand complexes. Immunity 2008;29:182–91.
27. TakedaK.The lipid A receptor. Adv Exp Med Biol 2009;667:53–8.
28. RansohoffRM, BrownMA.Innate immunity in the central nervous system. J Clin Invest 2012;122:1164–71.
29. RivestS.Molecular insights on the cerebral innate immune system. Brain Behav Immun 2003;17:13–19.
30. LehnardtS, MassillonL, FollettP, et al. Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci USA 2003;100:8514–19.
31. LehnardtS, LachanceC, PatriziS, et al. The Toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 2002;22:2478–86.
32. QinL, LiG, QianX, et al. Interactive role of the Toll-like receptor 4 and reactive oxygen species in LPS-induced microglia activation. Glia 2005;52:78–84.
33. BuchananMM, HutchinsonM, WatkinsLR, YinH.Toll-like receptor 4 in CNS pathologies. J Neurochem 2002;114:13–27.
34. BowmanCC, RasleyA, TranguchSL, MarriottI.Cultured astrocytes express Toll-like receptors for bacterial products. Glia 2003;43:281–91.
35. RollsA, ShechterR, LondonA, et al. Toll-like receptors modulate adult hippocampal neurogenesis. Nat Cell Biol 2007;9:1081–8.
36. TangSC, ArumugamTV, XuX, et al. Pivotal role for neuronal Toll-like receptors in ischemic brain injury and functional deficits. Proc Natl Acad Sci USA 2007;104:13798–803.
37. ShechterR, RonenA, RollsA, et al. Toll-like receptor 4 restricts retinal progenitor cell proliferation. J Cell Biol 2008;183:393–400.
38. MarosoM, BalossoS, RavizzaT, et al. Interleukin-1beta biosynthesis inhibition reduces acute seizures and drug resistant chronic epileptic activity in mice. Neurotherapeutics 2011;8:304–15.
39. SarnicoI, LanzillottaA, BenareseM, et al. NF-kappaB dimers in the regulation of neuronal survival. Int Rev Neurobiol 2009;85:351–62.
40. CasoJR, PradilloJM, HurtadoO, et al. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007;115:1599–608.
41. CasoJR, PradilloJM, HurtadoO, et al. Toll-like receptor 4 is involved in subacute stress-induced neuroinflammation and in the worsening of experimental stroke. Stroke 2008;39:1314–20.
42. ZhangJ, TakahashiHK, LiuK, et al. Anti-high mobility group box-1 monoclonal antibody protects the blood–brain barrier from ischemia-induced disruption in rats. Stroke 2011;42:1420–8.
43. YangH, LundbackP, OttossonL, et al. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol Med 2012;18:250–9.
44. YangH, HreggvidsdottirHS, PalmbladK, et al. A critical cysteine is required for HMGB1 binding to Toll-like receptor 4 and activation of macrophage cytokine release. Proc Natl Acad Sci USA 2010;107:11942–7.
45. HuttunenHJ, FagesC, Kuja-PanulaJ, RidleyAJ, RauvalaH.Receptor for advanced glycation end products-binding COOH-terminal motif of amphoterin inhibits invasive migration and metastasis. Cancer Res 2002;62:4805–11.
46. VenereauE, CasalgrandiM, SchiraldiM, et al. Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J Exp Med 2012;209:1519–28.
47. SakaguchiM, MurataH, YamamotoK, et al. TIRAP, an adaptor protein for TLR2/4, transduces a signal from RAGE phosphorylated upon ligand binding. PLoS One 2011;6:e23132.
48. FisherRS, van Emde BoasW, BlumeW, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 2005;46:470–2.
49. HaydonPG.GLIA: listening and talking to the synapse. Nat Rev Neurosci 2001;2(3):185–93.
50. PascualO, Ben AchourS, RostaingP, TrillerA, BessisA.Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci USA 2012;109:E197–205.
51. BergAT, ShinnarS.Complex febrile seizures. Epilepsia 1996;37:126–33.
52. CendesF, AndermannF, DubeauF, et al. Early childhood prolonged febrile convulsions, atrophy and sclerosis of mesial structures, and temporal lobe epilepsy: an MRI volumetric study. Neurology 1993;43:1083–7.
53. GorterJA, van VlietEA, AronicaE, et al. Potential new antiepileptogenic targets indicated by microarray analysis in a rat model for temporal lobe epilepsy. J Neurosci 2006;26:11083–110.
54. MajoresM, EilsJ, WiestlerOD, BeckerAJ.Molecular profiling of temporal lobe epilepsy: comparison of data from human tissue samples and animal models. Epilepsy Res 2004;60:173–8.
55. MarosoM, BalossoS, RavizzaT, et al. Toll-like receptor 4 and high-mobility group box-1 are involved in ictogenesis and can be targeted to reduce seizures. Nat Med 2010;16:413–19.
56. CaoL, TangaFY, DeleoJA.The contributing role of CD14 in Toll-like receptor 4 dependent neuropathic pain. Neuroscience 2009;158:896–903.
57. TangaFY, Nutile-McMenemyN, DeLeoJA.The CNS role of Toll-like receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci USA 2005;102:5856–61.
58. HutchinsonMR, ZhangY, BrownK, 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.
59. LewisSS, LoramLC, Hutchinson MR, et al. (+)-naloxone, an opioid-inactive Toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain 2012;13:498–506.
60. SorgeRE, LaCroix-FralishML, TuttleAH, et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci 2011;31:15450–4.
61. LandryRP, JacobsVL, Romero-SandovalEA, DeLeoJA.Propentofylline, a CNS glial modulator does not decrease pain in post-herpetic neuralgia patients: in vitro evidence for differential responses in human and rodent microglia and macrophages. Exp Neurol 2012;234:340–50.
62. MillerRJ, JungH, BhangooSK, WhiteFA.Cytokine and chemokine regulation of sensory neuron function. Handb Exp Pharmacol 2009;194:417–49.
63. FeldmanP, DueMR, RipschMS, KhannaR, WhiteFA.The persistent release of HMGB1 contributes to tactile hyperalgesia in a rodent model of neuropathic pain. J Neuroinflammation 2012;9:180.
64. BierhausA, HaslbeckKM, HumpertPM, et al. Loss of pain perception in diabetes is dependent on a receptor of the immunoglobulin superfamily. J Clin Invest 2004;114:1741–51.
65. ChacurM, MilliganED, GazdaLS, et al. A new model of sciatic inflammatory neuritis (SIN): induction of unilateral and bilateral mechanical allodynia following acute unilateral peri-sciatic immune activation in rats. Pain 2001;94:231–44.
66. O’ConnorKA, HansenMK, Rachal PughC, et al. Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects. Cytokine 2003;24:254–65.
67. ShibasakiM, SasakiM, MiuraM, et al. Induction of high mobility group box-1 in dorsal root ganglion contributes to pain hypersensitivity after peripheral nerve injury. Pain 2010;149:514–21.
68. TongW, WangW, HuangJ, et al. Spinal high-mobility group box 1 contributes to mechanical allodynia in a rat model of bone cancer pain. Biochem Biophys Res Comm 2010;395:572–6.
69. YamamuraY, SantaT, KotakiH, et al. Administration-route dependency of absorption of glycyrrhizin in rats: intraperitoneal administration dramatically enhanced bioavailability. Biol Pharmaceut Bull 1995;18:337–41.
70. TabuchiM, ImamuraS, KawakamiZ, IkarashiY, KaseY.The blood–brain barrier permeability of 18beta-glycyrrhetinic acid, a major metabolite of glycyrrhizin in glycyrrhiza root, a constituent of the traditional Japanese medicine yokukansan. Cellul Mol Neurobiol 2012;32:1139–46.
71. AngstMS, KoppertW, PahlI, ClarkDJ, SchmelzM.Short-term infusion of the mu-opioid agonist remifentanil in humans causes hyperalgesia during withdrawal. Pain 2003;106:49–57.
72. ArnerS, RawalN, GustafssonLL.Clinical experience of long-term treatment with epidural and intrathecal opioids – a nationwide survey. Acta Anaesthesiol Scand 1988;32:253–9.
73. SinglaA, StojanovicMP, ChenL, MaoJ.A differential diagnosis of hyperalgesia, toxicity, and withdrawal from intrathecal morphine infusion. Anesth Analg 2007;105:1816–19.
74. LaulinJP, CelerierE, LarcherA, Le MoalM, SimonnetG.Opiate tolerance to daily heroin administration: an apparent phenomenon associated with enhanced pain sensitivity. Neuroscience 1999;89:631–6.
75. WoolfCJ, FitzgeraldM.Lamina-specific alteration of C-fibre evoked activity by morphine in the dorsal horn of the rat spinal cord. Neurosci Lett 1981;25:37–41.
76. WatkinsLR, HutchinsonMR, RiceKC, MaierSF.The “toll” of opioid-induced glial activation: improving the clinical efficacy of opioids by targeting glia. Trends Pharmacol Sci 2009;30:581–91.
77. WhiteF, WilsonN.Opiate-induced hypernociception and chemokine receptors. Neuropharmacology 2010;58:35–7.
78. WilsonNM, JungH, RipschMS, MillerRJ, WhiteFA.CXCR4 signaling mediates morphine-induced tactile hyperalgesia. Brain Behav Immun 2011;25:565–73.
79. HasselstromJ, SaweJ. Morphine pharmacokinetics and metabolism in humans. Enterohepatic cycling and relative contribution of metabolites to active opioid concentrations. Clin Pharmacokinet 1993;24:344–54.
80. OsborneR, JoelS, TrewD, SlevinM.Morphine and metabolite behavior after different routes of morphine administration: demonstration of the importance of the active metabolite morphine-6-glucuronide. Clin Pharmacol Ther 1990;47:12–19.
81. SmithMT.Neuroexcitatory effects of morphine and hydromorphone: evidence implicating the 3-glucuronide metabolites. Clin Exp Pharmacol Physiol 2000;27:524–8.
82. YakshTL, NoueihedRY, DurantPA.Studies of the pharmacology and pathology of intrathecally administered 4-anilinopiperidine analogues and morphine in the rat and cat. Anesthesiology 1986;64:54–66.
83. LewisSS, HutchinsonMR, RezvaniN, et al. Evidence that intrathecal morphine-3-glucuronide may cause pain enhancement via Toll-like receptor 4/MD-2 and interleukin-1beta. Neuroscience 2010;165:569–83.
84. SongP, ZhaoZQ.The involvement of glial cells in the development of morphine tolerance. Neurosci Res 2001;39:281–6.
85. HutchinsonMR, ZhangY, ShridharM, et al. Evidence that opioids may have Toll-like receptor 4 and MD-2 effects. Brain Behav Immun 2010;24:83–95.
86. AndersenG, ChristrupL, SjogrenP.Relationships among morphine metabolism, pain and side effects during long-term treatment: an update. J Pain Symptom Manage 2003;25:74–91.
87. ChristrupLL.Morphine metabolites. Acta Anaesthesiol Scand 1997;41:116–22.
88. QinX, HouL, WangX.Lipopolysaccharide evoked peptide release by calcium-induced calcium release. Neuroreport 2004;15:1003–6.
89. DueMR, WilsonNM, FeldmanPF, et al. Increased functional expression of TLR4 following repeated morphine treatment contributes to opioid-induced hyperalgesia. In 41st Annual Society for Neuroscience Conference. Washington, DC; 2011.