Search tips
Search criteria 


Logo of neuroscibullNeuroscience Bulletin
Neurosci Bull. 2012 April; 28(2): 131–144.
Published online 2012 February 29. doi:  10.1007/s12264-012-1219-5
PMCID: PMC3347759

Emerging role of Toll-like receptors in the control of pain and itch


Toll-like receptors (TLRs) are germline-encoded pattern-recognition receptors that initiate innate immune responses by recognizing molecular structures shared by a wide range of pathogens, known as pathogen-associated molecular patterns (PAMPs). After tissue injury or cellular stress, TLRs also detect endogenous ligands known as danger-associated molecular patterns (DAMPs). TLRs are expressed in both non-neuronal and neuronal cell types in the central nervous system (CNS) and contribute to both infectious and non-infectious disorders in the CNS. Following tissue insult and nerve injury, TLRs (such as TLR2, TLR3, and TLR4) induce the activation of microglia and astrocytes and the production of the proinflammatory cytokines in the spinal cord, leading to the development and maintenance of inflammatory pain and neuropathic pain. In particular, primary sensory neurons, such as nociceptors, express TLRs (e.g., TLR4 and TLR7) to sense exogenous PAMPs and endogenous DAMPs released after tissue injury and cellular stress. These neuronal TLRs are new players in the processing of pain and itch by increasing the excitability of primary sensory neurons. Given the prevalence of chronic pain and itch and the suffering of affected people, insights into TLR signaling in the nervous system will open a new avenue for the management of clinical pain and itch.

Keywords: astrocytes, microglia, Toll-like receptor, pain, itch, danger-associated molecular patterns, pathogen-associated molecular patterns

Contributor Information

Tong Liu, Phone: +1-617-7328852, Fax: +1-617-7302801, gro.srentrap@5uilt.

Ru-Rong Ji, Phone: +1-617-7328852, Fax: +1-617-7302801, ude.dravrah.hwb.suez@ijrr.


[1] Akira S., Uematsu S., Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801. doi: 10.1016/j.cell.2006.02.015. [PubMed] [Cross Ref]
[2] Mills K.H. TLR-dependent T cell activation in autoimmunity. Nat Rev Immunol. 2011;11:807–822. [PubMed]
[3] Anderson K.V., Jurgens G., Nusslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: genetic studies on the role of the Toll gene product. Cell. 1985;42:779–789. doi: 10.1016/0092-8674(85)90274-0. [PubMed] [Cross Ref]
[4] Lemaitre B., Nicolas E., Michaut L., Reichhart J.M., Hoffmann J.A. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–983. doi: 10.1016/S0092-8674(00)80172-5. [PubMed] [Cross Ref]
[5] Medzhitov R., Janeway C., Jr. Innate immune recognition: mechanisms and pathways. Immunol Rev. 2000;173:89–97. doi: 10.1034/j.1600-065X.2000.917309.x. [PubMed] [Cross Ref]
[6] Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol. 2010;11:373–384. doi: 10.1038/ni.1863. [PubMed] [Cross Ref]
[7] Oosting M., Ter H.H., Sturm P., Adema G.J., Kullberg B.J., van der Meer J.W., et al. TLR1/TLR2 heterodimers play an important role in the recognition of Borrelia spirochetes. PLoS One. 2011;6:e25998. doi: 10.1371/journal.pone.0025998. [PMC free article] [PubMed] [Cross Ref]
[8] Triantafilou M., Uddin A., Maher S., Charalambous N., Hamm T.S., Alsumaiti A., et al. Anthrax toxin evades Toll-like receptor recognition, whereas its cell wall components trigger activation via TLR2/6 heterodimers. Cell Microbiol. 2007;9:2880–2892. doi: 10.1111/j.1462-5822.2007.01003.x. [PubMed] [Cross Ref]
[9] Alexopoulou L., Thomas V., Schnare M., Lobet Y., Anguita J., Schoen R.T., et al. Hyporesponsiveness to vaccination with Borrelia burgdorferi OspA in humans and in TLR1- and TLR2-deficient mice. Nat Med. 2002;8:878–884. [PubMed]
[10] Yamamoto M., Sato S., Mori K., Hoshino K., Takeuchi O., Takeda K., et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 2002;169:6668–6672. [PubMed]
[11] Diebold S.S., Kaisho T., Hemmi H., Akira S., Reis e Sousa C. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303:1529–1531. doi: 10.1126/science.1093616. [PubMed] [Cross Ref]
[12] Town T., Jeng D., Alexopoulou L., Tan J., Flavell R.A. Microglia recognize double-stranded RNA via TLR3. J Immunol. 2006;176:3804–3812. [PubMed]
[13] Alexopoulou L., Holt A.C., Medzhitov R., Flavell R.A. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–738. doi: 10.1038/35099560. [PubMed] [Cross Ref]
[14] Heil F., Hemmi H., Hochrein H., Ampenberger F., Kirschning C., Akira S., et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–1529. doi: 10.1126/science.1093620. [PubMed] [Cross Ref]
[15] Shimazu R., Akashi S., Ogata H., Nagai Y., Fukudome K., Miyake K., et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med. 1999;189:1777–1782. doi: 10.1084/jem.189.11.1777. [PMC free article] [PubMed] [Cross Ref]
[16] Poltorak A., He X., Smirnova I., Liu M.Y., Van H.C., Du X., et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–2088. doi: 10.1126/science.282.5396.2085. [PubMed] [Cross Ref]
[17] Hayashi F., Smith K.D., Ozinsky A., Hawn T.R., Yi E.C., Goodlett D.R., et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410:1099–1103. doi: 10.1038/35074106. [PubMed] [Cross Ref]
[18] Hemmi H., Takeuchi O., Kawai T., Kaisho T., Sato S., Sanjo H., et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–745. doi: 10.1038/35047123. [PubMed] [Cross Ref]
[19] Krieg A.M. CpG motifs in bacterial DNA and their immune effects. Annu Rev Immunol. 2002;20:709–760. doi: 10.1146/annurev.immunol.20.100301.064842. [PubMed] [Cross Ref]
[20] Yarovinsky F., Zhang D., Andersen J.F., Bannenberg G.L., Serhan C.N., Hayden M.S., et al. TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science. 2005;308:1626–1629. doi: 10.1126/science.1109893. [PubMed] [Cross Ref]
[21] Okamura Y., Watari M., Jerud E.S., Young D.W., Ishizaka S.T., Rose J., et al. The extra domain A of fibronectin activates Toll-like receptor4. J Biol Chem. 2001;276:10229–10233. doi: 10.1074/jbc.M100099200. [PubMed] [Cross Ref]
[22] Imai Y., Kuba K., Neely G.G., Yaghubian-Malhami R., Perkmann T., van L.G., et al. Identification of oxidative stress and Toll-like receptor 4 signaling as a key pathway of acute lung injury. Cell. 2008;133:235–249. doi: 10.1016/j.cell.2008.02.043. [PubMed] [Cross Ref]
[23] Jiang D., Liang J., Fan J., Yu S., Chen S., Luo Y., et al. Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nat Med. 2005;11:1173–1179. doi: 10.1038/nm1315. [PubMed] [Cross Ref]
[24] Midwood K., Sacre S., Piccinini A.M., Inglis J., Trebaul A., Chan E., et al. Tenascin-C is an endogenous activator of Toll-like receptor 4 that is essential for maintaining inflammation in arthritic joint disease. Nat Med. 2009;15:774–780. doi: 10.1038/nm.1987. [PubMed] [Cross Ref]
[25] West X.Z., Malinin N.L., Merkulova A.A., Tischenko M., Kerr B.A., Borden E.C., et al. Oxidative stress induces angiogenesis by activating TLR2 with novel endogenous ligands. Nature. 2010;467:972–976. doi: 10.1038/nature09421. [PMC free article] [PubMed] [Cross Ref]
[26] Tian J., Avalos A.M., Mao S.Y., Chen B., Senthil K., Wu H., et al. Tolllike receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 2007;8:487–496. doi: 10.1038/ni1457. [PubMed] [Cross Ref]
[27] Biragyn A., Ruffini P.A., Leifer C.A., Klyushnenkova E., Shakhov A., Chertov O., et al. Toll-like receptor 4-dependent activation of dendritic cells by beta-defensin 2. Science. 2002;298:1025–1029. doi: 10.1126/science.1075565. [PubMed] [Cross Ref]
[28] Vabulas R.M., Wagner H., Schild H. Heat shock proteins as ligands of toll-like receptors. Curr Top Microbiol Immunol. 2002;270:169–184. doi: 10.1007/978-3-642-59430-4_11. [PubMed] [Cross Ref]
[29] Kariko K., Ni H., Capodici J., Lamphier M., Weissman D. mRNA is an endogenous ligand for Toll-like receptor 3. J Biol Chem. 2004;279:12542–12550. doi: 10.1074/jbc.M310175200. [PubMed] [Cross Ref]
[30] Takeuchi O., Akira S. Pattern recognition receptors and inflammation. Cell. 2010;140:805–820. doi: 10.1016/j.cell.2010.01.022. [PubMed] [Cross Ref]
[31] Akira S., Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511. doi: 10.1038/nri1391. [PubMed] [Cross Ref]
[32] Gao Y.J., Zhang L., Samad O.A., Suter M.R., Yasuhiko K., Xu Z.Z., et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 2009;29:4096–4108. doi: 10.1523/JNEUROSCI.3623-08.2009. [PMC free article] [PubMed] [Cross Ref]
[33] Takeda K., Akira S. TLR signaling pathways. Semin Immunol. 2004;16:3–9. doi: 10.1016/j.smim.2003.10.003. [PubMed] [Cross Ref]
[34] Yamamoto M., Sato S., Hemmi H., Hoshino K., Kaisho T., Sanjo H., et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003;301:640–643. doi: 10.1126/science.1087262. [PubMed] [Cross Ref]
[35] Okun E., Griffioen K.J., Mattson M.P. Toll-like receptor signaling in neural plasticity and disease. Trends Neurosci. 2011;34(5):269–281. doi: 10.1016/j.tins.2011.02.005. [PMC free article] [PubMed] [Cross Ref]
[36] Buchanan M.M., Hutchinson M., Watkins L.R., Yin H. Toll-like receptor 4 in CNS pathologies. J Neurochem. 2010;114:13–27. [PMC free article] [PubMed]
[37] Lehnardt S. Innate immunity and neuroinflammation in the CNS: the role of microglia in Toll-like receptor-mediated neuronal injury. Glia. 2010;58:253–263. [PubMed]
[38] van Noort J.M., Bsibsi M. Toll-like receptors in the CNS: implications for neurodegeneration and repair. Prog Brain Res. 2009;175:139–148. doi: 10.1016/S0079-6123(09)17509-X. [PubMed] [Cross Ref]
[39] Basbaum A.I., Bautista D.M., Scherrer G., Julius D. Cellular and molecular mechanisms of pain. Cell. 2009;139:267–284. doi: 10.1016/j.cell.2009.09.028. [PMC free article] [PubMed] [Cross Ref]
[40] Nicotra L, Loram LC, Watkins LR, Hutchinson MR. Toll-like receptors in chronic pain. Exp Neurol 2011. [Epub ahead of print] [PMC free article] [PubMed]
[41] Suh H.S., Brosnan C.F., Lee S.C. Toll-like receptors in CNS viral infections. Curr Top Microbiol Immunol. 2009;336:63–81. doi: 10.1007/978-3-642-00549-7_4. [PubMed] [Cross Ref]
[42] Caso J.R., Pradillo J.M., Hurtado O., Lorenzo P., Moro M. L. I. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation. 2007;115:1599–1608. doi: 10.1161/CIRCULATIONAHA.106.603431. [PubMed] [Cross Ref]
[43] Tahara K., Kim H.D., Jin J.J., Maxwell J.A., Li L., Fukuchi K. Role of toll-like receptor signalling in Abeta uptake and clearance. Brain. 2006;129:3006–3019. doi: 10.1093/brain/awl249. [PMC free article] [PubMed] [Cross Ref]
[44] Prinz M., Garbe F., Schmidt H., Mildner A., Gutcher I., Wolter K., et al. Innate immunity mediated by TLR9 modulates pathogenicity in an animal model of multiple sclerosis. J Clin Invest. 2006;116:456–464. doi: 10.1172/JCI26078. [PubMed] [Cross Ref]
[45] Kim D., Lee S., Lee S.J. Toll-like receptors in peripheral nerve injury and neuropathic pain. Curr Top Microbiol Immunol. 2009;336:169–186. doi: 10.1007/978-3-642-00549-7_10. [PubMed] [Cross Ref]
[46] Guo L.H., Schluesener H.J. The innate immunity of the central nervous system in chronic pain: the role of Toll-like receptors. Cell Mol Life Sci. 2007;64:1128–1136. doi: 10.1007/s00018-007-6494-3. [PubMed] [Cross Ref]
[47] Tanga F.Y., Nutile-McMenemy N., Deleo J.A. The CNS role of Tolllike receptor 4 in innate neuroimmunity and painful neuropathy. Proc Natl Acad Sci U S A. 2005;102:5856–5861. doi: 10.1073/pnas.0501634102. [PubMed] [Cross Ref]
[48] Kim D., Kim M.A., Cho I.H., Kim M.S., Lee S., Jo E.K., 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;282:14975–14983. doi: 10.1074/jbc.M607277200. [PubMed] [Cross Ref]
[49] Obata K., Katsura H., Miyoshi K., Kondo T., Yamanaka H., Kobayashi K., et al. Toll-like receptor 3 contributes to spinal glial activation and tactile allodynia after nerve injury. J Neurochem. 2008;105:2249–2259. doi: 10.1111/j.1471-4159.2008.05353.x. [PubMed] [Cross Ref]
[50] Sorge R.E., LaCroix-Fralish M.L., Tuttle A.H., Sotocinal S.G., Austin J.S., Ritchie J., et al. Spinal cord Toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci. 2011;31:15450–15454. doi: 10.1523/JNEUROSCI.3859-11.2011. [PMC free article] [PubMed] [Cross Ref]
[51] Saito O., Svensson C.I., Buczynski M.W., Wegner K., Hua X.Y., Codeluppi S., et al. Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. Br J Pharmacol. 2010;160:1754–1764. doi: 10.1111/j.1476-5381.2010.00811.x. [PMC free article] [PubMed] [Cross Ref]
[52] Mei X.P., Zhou Y., Wang W., Tang J., Wang W., Zhang H., et al. Ketamine depresses Toll-like receptor 3 signaling in spinal microglia in a rat model of neuropathic pain. Neurosignals. 2011;19:44–53. doi: 10.1159/000324293. [PubMed] [Cross Ref]
[53] Christianson C.A., Dumlao D.S., Stokes J.A., Dennis E.A., Svensson C.I., Corr M., et al. Spinal TLR4 mediates the transition to a persistent mechanical hypersensitivity after the resolution of inflammation in serum-transferred arthritis. Pain. 2011;152:2881–2891. doi: 10.1016/j.pain.2011.09.020. [PMC free article] [PubMed] [Cross Ref]
[54] Wu F.X., Bian J.J., Miao X.R., Huang S.D., Xu X.W., Gong D.J., et al. Intrathecal siRNA against Toll-like receptor 4 reduces nociception in a rat model of neuropathic pain. Int J Med Sci. 2010;7:251–259. doi: 10.7150/ijms.7.251. [PMC free article] [PubMed] [Cross Ref]
[55] Lan L.S., Ping Y.J., Na W.L., Miao J., Cheng Q.Q., Ni M.Z., et al. Down-regulation of Toll-like receptor 4 gene expression by short interfering RNA attenuates bone cancer pain in a rat model. Mol Pain. 2010;6:2. doi: 10.1186/1744-8069-6-2. [PMC free article] [PubMed] [Cross Ref]
[56] Kuang X., Huang Y., Gu H.F., Zu X.Y., Zou W.Y., Song Z.B., et al. Effects of intrathecal epigallocatechin gallate, an inhibitor of Tolllike receptor 4, on chronic neuropathic pain in rats. Eur J Pharmacol. 2012;676:51–56. doi: 10.1016/j.ejphar.2011.11.037. [PubMed] [Cross Ref]
[57] Qi J., Buzas K., Fan H., Cohen J.I., Wang K., Mont E., et al. Painful pathways induced by TLR stimulation of dorsal root ganglion neurons. J Immunol. 2011;186:6417–6426. doi: 10.4049/jimmunol.1001241. [PMC free article] [PubMed] [Cross Ref]
[58] Xiao H.S., Huang Q.H., Zhang F.X., Bao L., Lu Y.J., Guo C., et al. Identification of gene expression profile of dorsal root ganglion in the rat peripheral axotomy model of neuropathic pain. Proc Natl Acad Sci U S A. 2002;99:8360–8365. doi: 10.1073/pnas.122231899. [PubMed] [Cross Ref]
[59] Hokfelt T., Zhang X., Wiesenfeld-Hallin Z. Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends Neurosci. 1994;17:22–30. doi: 10.1016/0166-2236(94)90031-0. [PubMed] [Cross Ref]
[60] Woolf C.J., Salter M.W. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769. doi: 10.1126/science.288.5472.1765. [PubMed] [Cross Ref]
[61] Ji R.R., Kohno T., Moore K.A., Woolf C.J. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705. doi: 10.1016/j.tins.2003.09.017. [PubMed] [Cross Ref]
[62] Tao Y.X. Dorsal horn alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking in inflammatory pain. Anesthesiology. 2010;112:1259–1265. doi: 10.1097/ALN.0b013e3181d3e1ed. [PMC free article] [PubMed] [Cross Ref]
[63] Stucky C.L., Gold M.S., Zhang X. Mechanisms of pain. Proc Natl Acad Sci U S A. 2001;98:11845–11846. doi: 10.1073/pnas.211373398. [PubMed] [Cross Ref]
[64] Luo F., Wang J.Y. Neuronal nociceptive responses in thalamocortical pathways. Neurosci Bull. 2009;25:289–295. doi: 10.1007/s12264-009-0908-1. [PMC free article] [PubMed] [Cross Ref]
[65] Liu M.G., Chen J. Roles of the hippocampal formation in pain information processing. Neurosci Bull. 2009;25:237–266. doi: 10.1007/s12264-009-0905-4. [PMC free article] [PubMed] [Cross Ref]
[66] Li H.L., Qin L.Y., Wan Y. Astrocyte: a new star in pain research. Sheng Li Ke Xue Jin Zhan. 2003;34:45–48. [PubMed]
[67] Liu F.Y., Sun Y.N., Wang F.T., Li Q., Su L., Zhao Z.F., et al. Activation of satellite glial cells in lumbar dorsal root ganglia contributes to neuropathic pain after spinal nerve ligation. Brain Res. 2012;1427:65–77. doi: 10.1016/j.brainres.2011.10.016. [PubMed] [Cross Ref]
[68] Suter M.R., Wen Y.R., Decosterd I., Ji R.R. Do glial cells control pain? Neuron Glia Biol. 2007;3:255–268. doi: 10.1017/S1740925X08000100. [PMC free article] [PubMed] [Cross Ref]
[69] Ji R.R., Suter M.R. p38 MAPK, microglial signaling, and neuropathic pain. Mol Pain. 2007;3:33. doi: 10.1186/1744-8069-3-33. [PMC free article] [PubMed] [Cross Ref]
[70] Gao Y.J., Ji R.R. Targeting astrocyte signaling for chronic pain. Neurotherapeutics. 2010;7:482–493. doi: 10.1016/j.nurt.2010.05.016. [PMC free article] [PubMed] [Cross Ref]
[71] Gao Y.J., Ji R.R. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 2010;126:56–68. doi: 10.1016/j.pharmthera.2010.01.002. [PMC free article] [PubMed] [Cross Ref]
[72] 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. doi: 10.1016/ [PMC free article] [PubMed] [Cross Ref]
[73] Romero-Sandoval E.A., Horvath R.J., Deleo J.A. Neuroimmune interactions and pain: focus on glial-modulating targets. Curr Opin Investig Drugs. 2008;9:726–734. [PMC free article] [PubMed]
[74] Zhang F.Y., Wan Y., Zhang Z.K., Light A.R., Fu K.Y. Peripheral formalin injection induces long-lasting increases in cyclooxygenase 1 expression by microglia in the spinal cord. J Pain. 2007;8:110–117. doi: 10.1016/j.jpain.2006.06.006. [PubMed] [Cross Ref]
[75] Ren K., Dubner R. Interactions between the immune and nervous systems in pain. Nat Med. 2010;16:1267–1276. doi: 10.1038/nm.2234. [PMC free article] [PubMed] [Cross Ref]
[76] Scholz J., Woolf C.J. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361–1368. doi: 10.1038/nn1992. [PubMed] [Cross Ref]
[77] Tsuda M., Inoue K., Salter M.W. Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends Neurosci. 2005;28:101–107. doi: 10.1016/j.tins.2004.12.002. [PubMed] [Cross Ref]
[78] Guo W., Wang H., Watanabe M., Shimizu K., Zou S., LaGraize S.C., et al. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci. 2007;27:6006–6018. doi: 10.1523/JNEUROSCI.0176-07.2007. [PMC free article] [PubMed] [Cross Ref]
[79] Smith H.S. Activated microglia in nociception. Pain Physician. 2010;13:295–304. [PubMed]
[80] Zhou D., Chen M.L., Zhang Y.Q., Zhao Z.Q. Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats. J Neurosci. 2010;30:8042–8047. doi: 10.1523/JNEUROSCI.5377-09.2010. [PubMed] [Cross Ref]
[81] Song P., Zhao Z.Q. The involvement of glial cells in the development of morphine tolerance. Neurosci Res. 2001;39:281–286. doi: 10.1016/S0168-0102(00)00226-1. [PubMed] [Cross Ref]
[82] Ji R.R., Gereau R.W., Malcangio M., Strichartz G.R. MAP kinase and pain. Brain Res Rev. 2009;60:135–148. doi: 10.1016/j.brainresrev.2008.12.011. [PMC free article] [PubMed] [Cross Ref]
[83] Zhou L.J., Yang T., Wei X., Liu Y., Xin W.J., Chen Y., et al. Brainderived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat. Brain Behav Immun. 2011;25:322–334. doi: 10.1016/j.bbi.2010.09.025. [PubMed] [Cross Ref]
[84] Xu J.T., Xin W.J., Wei X.H., Wu C.Y., Ge Y.X., Liu Y.L., et al. p38 activation in uninjured primary afferent neurons and in spinal microglia contributes to the development of neuropathic pain induced by selective motor fiber injury. Exp Neurol. 2007;204:355–365. doi: 10.1016/j.expneurol.2006.11.016. [PubMed] [Cross Ref]
[85] Kawasaki Y., Zhang L., Cheng J.K., Ji R.R. 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. 2008;28:5189–5194. doi: 10.1523/JNEUROSCI.3338-07.2008. [PMC free article] [PubMed] [Cross Ref]
[86] Coull J.A., Beggs S., Boudreau D., Boivin D., Tsuda M., Inoue K., et al. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438:1017–1021. doi: 10.1038/nature04223. [PubMed] [Cross Ref]
[87] Li J., Xie W., Zhang J.M., Baccei M.L. Peripheral nerve injury sensitizes neonatal dorsal horn neurons to tumor necrosis factor-alpha. Mol Pain. 2009;5:10. doi: 10.1186/1744-8069-5-10. [PMC free article] [PubMed] [Cross Ref]
[88] Zhou L.J., Zhong Y., Ren W.J., Li Y.Y., Zhang T., Liu X.G. BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. Exp Neurol. 2008;212:507–514. doi: 10.1016/j.expneurol.2008.04.034. [PubMed] [Cross Ref]
[89] Liu Y.L., Zhou L.J., Hu N.W., Xu J.T., Wu C.Y., Zhang T., et al. 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. 2007;52:708–715. doi: 10.1016/j.neuropharm.2006.09.011. [PubMed] [Cross Ref]
[90] Park C.K., Lu N., Xu Z.Z., Liu T., Serhan C.N., Ji R.R. Resolving TRPV1- and TNF-alpha-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J Neurosci. 2011;31:15072–15085. doi: 10.1523/JNEUROSCI.2443-11.2011. [PMC free article] [PubMed] [Cross Ref]
[91] Bsibsi M., Ravid R., Gveric D., van Noort J.M. Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol. 2002;61:1013–1021. [PubMed]
[92] Olson J.K., Miller S.D. Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol. 2004;173:3916–3924. [PubMed]
[93] Iliev A.I., Stringaris A.K., Nau R., Neumann H. Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9) FASEB J. 2004;18:412–414. [PubMed]
[94] Dalpke A.H., Schafer M.K., Frey M., Zimmermann S., Tebbe J., Weihe E., et al. Immunostimulatory CpG-DNA activates murine microglia. J Immunol. 2002;168:4854–4863. [PubMed]
[95] Butchi N.B., Du M., Peterson K.E. Interactions between TLR7 and TLR9 agonists and receptors regulate innate immune responses by astrocytes and microglia. Glia. 2010;58:650–664. [PMC free article] [PubMed]
[96] Qin L., Li G., Qian X., Liu Y., Wu X., Liu B., et al. Interactive role of the toll-like receptor 4 and reactive oxygen species in LPSinduced microglia activation. Glia. 2005;52:78–84. doi: 10.1002/glia.20225. [PubMed] [Cross Ref]
[97] Clark A.K., Staniland A.A., Marchand F., Kaan T.K., McMahon S.B., Malcangio M. P2X7-dependent release of interleukin-1beta and nociception in the spinal cord following lipopolysaccharide. J Neurosci. 2010;30:573–582. doi: 10.1523/JNEUROSCI.3295-09.2010. [PMC free article] [PubMed] [Cross Ref]
[98] Sugama S., Takenouchi T., Fujita M., Conti B., Hashimoto M. Differential microglial activation between acute stress and lipopolysaccharide treatment. J Neuroimmunol. 2009;207:24–31. doi: 10.1016/j.jneuroim.2008.11.007. [PubMed] [Cross Ref]
[99] Cao L., Tanga F.Y., Deleo J.A. The contributing role of CD14 in tolllike receptor 4 dependent neuropathic pain. Neuroscience. 2009;158:896–903. doi: 10.1016/j.neuroscience.2008.10.004. [PMC free article] [PubMed] [Cross Ref]
[100] Raghavendra V., Tanga F.Y., Deleo J.A. Complete Freunds adjuvantinduced peripheral inflammation evokes glial activation and proin-flammatory cytokine expression in the CNS. Eur J Neurosci. 2004;20:467–473. doi: 10.1111/j.1460-9568.2004.03514.x. [PubMed] [Cross Ref]
[101] Wen Y.R., Tan P.H., Cheng J.K., Liu Y.C., Ji R.R. Microglia: a promising target for treating neuropathic and postoperative pain, and morphine tolerance. J Formos Med Assoc. 2011;110:487–494. doi: 10.1016/S0929-6646(11)60074-0. [PMC free article] [PubMed] [Cross Ref]
[102] Matsui T., Svensson C.I., Hirata Y., Mizobata K., Hua X.Y., Yaksh T.L. Release of prostaglandin E(2) and nitric oxide from spinal microglia is dependent on activation of p38 mitogen-activated protein kinase. Anesth Analg. 2010;111:554–560. doi: 10.1213/ANE.0b013e3181e3a2a2. [PubMed] [Cross Ref]
[103] Dityatev A., Rusakov D.A. Molecular signals of plasticity at the tetrapartite synapse. Curr Opin Neurobiol. 2011;21:353–359. doi: 10.1016/j.conb.2010.12.006. [PMC free article] [PubMed] [Cross Ref]
[104] Petzold G.C., Murthy V.N. Role of astrocytes in neurovascular coupling. Neuron. 2011;71:782–797. doi: 10.1016/j.neuron.2011.08.009. [PubMed] [Cross Ref]
[105] Gao Y.J., Ji R.R. Activation of JNK pathway in persistent pain. Neurosci Lett. 2008;437:180–183. doi: 10.1016/j.neulet.2008.03.017. [PMC free article] [PubMed] [Cross Ref]
[106] Ji R.R., Kawasaki Y., Zhuang Z.Y., Wen Y.R., Decosterd I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: review of current evidence with focus on bFGF/JNK pathway. Neuron Glia Biol. 2006;2:259–269. doi: 10.1017/S1740925X07000403. [PMC free article] [PubMed] [Cross Ref]
[107] Jiang F., Liu T., Cheng M., Pang X.Y., Bai Z.T., Zhou J.J., et al. Spinal astrocyte and microglial activation contributes to rat pain-related behaviors induced by the venom of scorpion Buthus martensi Karch. Eur J Pharmacol. 2009;623:52–64. doi: 10.1016/j.ejphar.2009.09.028. [PubMed] [Cross Ref]
[108] Kawasaki Y., Xu Z.Z., Wang X., Park J.Y., Zhuang Z.Y., Tan P.H., et al. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med. 2008;14:331–336. doi: 10.1038/nm1723. [PMC free article] [PubMed] [Cross Ref]
[109] Gao Y.J., Xu Z.Z., Liu Y.C., Wen Y.R., Decosterd I., Ji R.R. 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. 2010;148:309–319. doi: 10.1016/j.pain.2009.11.017. [PMC free article] [PubMed] [Cross Ref]
[110] Tsuda M., Kohro Y., Yano T., Tsujikawa T., Kitano J., Tozaki-Saitoh H., et al. JAK-STAT3 pathway regulates spinal astrocyte proliferation and neuropathic pain maintenance in rats. Brain. 2011;134:1127–1139. doi: 10.1093/brain/awr025. [PMC free article] [PubMed] [Cross Ref]
[111] Wei F., Guo W., Zou S., Ren K., Dubner R. Supraspinal glialneuronal interactions contribute to descending pain facilitation. J Neurosci. 2008;28:10482–10495. doi: 10.1523/JNEUROSCI.3593-08.2008. [PMC free article] [PubMed] [Cross Ref]
[112] Ji R.R., Strichartz G. Cell signaling and the genesis of neuropathic pain. Sci STKE. 2004;2004:reE14. doi: 10.1126/stke.2522004re14. [PubMed] [Cross Ref]
[113] Ji R.R., Xu Z.Z., Wang X., Lo E.H. Matrix metalloprotease regulation of neuropathic pain. Trends Pharmacol Sci. 2009;30:336–340. doi: 10.1016/ [PMC free article] [PubMed] [Cross Ref]
[114] Wang W., Mei X.P., Wei Y.Y., Zhang M.M., Zhang T., Wang W., et al. Neuronal NR2B-containing NMDA receptor mediates spinal astrocytic c-Jun N-terminal kinase activation in a rat model of neuropathic pain. Brain Behav Immun. 2011;25:1355–1366. doi: 10.1016/j.bbi.2011.04.002. [PubMed] [Cross Ref]
[115] Ren K., Dubner R. Neuron-glia crosstalk gets serious: role in pain hypersensitivity. Curr Opin Anaesthesiol. 2008;21:570–579. doi: 10.1097/ACO.0b013e32830edbdf. [PMC free article] [PubMed] [Cross Ref]
[116] Ren K., Torres R. Role of interleukin-1beta during pain and inflammation. Brain Res Rev. 2009;60:57–64. doi: 10.1016/j.brainresrev.2008.12.020. [PMC free article] [PubMed] [Cross Ref]
[117] Farina C., Aloisi F., Meinl E. Astrocytes are active players in cerebral innate immunity. Trends Immunol. 2007;28:138–145. doi: 10.1016/ [PubMed] [Cross Ref]
[118] Carpentier P.A., Begolka W.S., Olson J.K., Elhofy A., Karpus W.J., Miller S.D. Differential activation of astrocytes by innate and adaptive immune stimuli. Glia. 2005;49:360–374. doi: 10.1002/glia.20117. [PubMed] [Cross Ref]
[119] Scumpia P.O., Kelly K.M., Reeves W.H., Stevens B.R. Doublestranded RNA signals antiviral and inflammatory programs and dysfunctional glutamate transport in TLR3-expressing astrocytes. Glia. 2005;52:153–162. doi: 10.1002/glia.20234. [PubMed] [Cross Ref]
[120] Kim H., Yang E., Lee J., Kim S.H., Shin J.S., Park J.Y., et al. Doublestranded RNA mediates interferon regulatory factor 3 activation and interleukin-6 production by engaging Toll-like receptor 3 in human brain astrocytes. Immunology. 2008;124:480–488. doi: 10.1111/j.1365-2567.2007.02799.x. [PubMed] [Cross Ref]
[121] Bsibsi M., Persoon-Deen C., Verwer R.W., Meeuwsen S., Ravid R., van Noort J.M. Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia. 2006;53:688–695. doi: 10.1002/glia.20328. [PubMed] [Cross Ref]
[122] Gorina R., Font-Nieves M., Marquez-Kisinousky L., Santalucia T., Planas A.M. Astrocyte TLR4 activation induces a proinflammatory environment through the interplay between MyD88-dependent NFkappaB signaling, MAPK, and Jak1/Stat1 pathways. Glia. 2011;59:242–255. doi: 10.1002/glia.21094. [PubMed] [Cross Ref]
[123] Bowman C.C., Rasley A., Tranguch S.L., Marriott I. Cultured astrocytes express toll-like receptors for bacterial products. Glia. 2003;43:281–291. doi: 10.1002/glia.10256. [PubMed] [Cross Ref]
[124] Hanke M.L., Kielian T. Toll-like receptors in health and disease in the brain: mechanisms and therapeutic potential. Clin Sci (Lond) 2011;121:367–387. doi: 10.1042/CS20110164. [PMC free article] [PubMed] [Cross Ref]
[125] Ji R.R., Gao Y.J. Astrocyte signaling in neuropathic pain. Glia. 2011;59:S35–36. doi: 10.1002/glia.21074. [Cross Ref]
[126] Wadachi R., Hargreaves K.M. Trigeminal nociceptors express TLR-4 and CD14: a mechanism for pain due to infection. J Dent Res. 2006;85:49–53. doi: 10.1177/154405910608500108. [PMC free article] [PubMed] [Cross Ref]
[127] Ferraz C.C., Henry M.A., Hargreaves K.M., Diogenes A. Lipopolysaccharide from Porphyromonas gingivalis sensitizes capsaicinsensitive nociceptors. J Endod. 2011;37:45–48. doi: 10.1016/j.joen.2007.07.001. [PMC free article] [PubMed] [Cross Ref]
[128] Diogenes A., Ferraz C.C., Akopian A.N., Henry M.A., Hargreaves K.M. LPS sensitizes TRPV1 via activation of TLR4 in trigeminal sensory neurons. J Dent Res. 2011;90:759–764. doi: 10.1177/0022034511400225. [PubMed] [Cross Ref]
[129] Acosta C., Davies A. Bacterial lipopolysaccharide regulates nociceptin expression in sensory neurons. J Neurosci Res. 2008;86:1077–1086. doi: 10.1002/jnr.21565. [PubMed] [Cross Ref]
[130] Liu T., Xu Z.Z., Park C.K., Berta T., Ji R.R. Toll-like receptor 7 mediates pruritus. Nat Neurosci. 2010;13:1460–1462. doi: 10.1038/nn.2683. [PMC free article] [PubMed] [Cross Ref]
[131] Ikoma A., Steinhoff M., Stander S., Yosipovitch G., Schmelz M. The neurobiology of itch. Nat Rev Neurosci. 2006;7:535–547. doi: 10.1038/nrn1950. [PubMed] [Cross Ref]
[132] Bieber T. Atopic dermatitis. N Engl J Med. 2008;358:1483–1494. doi: 10.1056/NEJMra074081. [PubMed] [Cross Ref]
[133] Reich A., Szepietowski J.C. Mediators of pruritus in psoriasis. Mediators Inflamm. 2007;2007:64727. doi: 10.1155/2007/64727. [PMC free article] [PubMed] [Cross Ref]
[134] Kremer A.E., Martens J.J., Kulik W., Rueff F., Kuiper E.M., van Buuren H.R., et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology. 2010;139:1008–1018. doi: 10.1053/j.gastro.2010.05.009. [PubMed] [Cross Ref]
[135] Cassano N., Tessari G., Vena G.A., Girolomoni G. Chronic pruritus in the absence of specific skin disease: an update on pathophysiology, diagnosis, and therapy. Am J Clin Dermatol. 2010;11:399–411. doi: 10.2165/11317620-000000000-00000. [PubMed] [Cross Ref]
[136] Yamaoka H., Sasaki H., Yamasaki H., Ogawa K., Ohta T., Furuta H., et al. Truncal pruritus of unknown origin may be a symptom of diabetic polyneuropathy. Diabetes Care. 2010;33:150–155. doi: 10.2337/dc09-0632. [PMC free article] [PubMed] [Cross Ref]
[137] Paus R., Schmelz M., Biro T., Steinhoff M. Frontiers in pruritus research: scratching the brain for more effective itch therapy. J Clin Invest. 2006;116:1174–1186. doi: 10.1172/JCI28553. [PMC free article] [PubMed] [Cross Ref]
[138] Imamachi N., Park G.H., Lee H., Anderson D.J., Simon M.I., Basbaum A.I., et al. TRPV1-expressing primary afferents generate behavioral responses to pruritogens via multiple mechanisms. Proc Natl Acad Sci U S A. 2009;106:11330–11335. doi: 10.1073/pnas.0905605106. [PubMed] [Cross Ref]
[139] Mishra S.K., Tisel S.M., Orestes P., Bhangoo S.K., Hoon M.A. TRPV1-lineage neurons are required for thermal sensation. EMBO J. 2011;30:582–593. doi: 10.1038/emboj.2010.325. [PubMed] [Cross Ref]
[140] Sun Y.G., Zhao Z.Q., Meng X.L., Yin J., Liu X.Y., Chen Z.F. Cellular basis of itch sensation. Science. 2009;325:1531–1534. doi: 10.1126/science.1174868. [PMC free article] [PubMed] [Cross Ref]
[141] Sun Y.G., Chen Z.F. A gastrin-releasing peptide receptor mediates the itch sensation in the spinal cord. Nature. 2007;448:700–703. doi: 10.1038/nature06029. [PubMed] [Cross Ref]
[142] Hemmi H., Kaisho T., Takeuchi O., Sato S., Sanjo H., Hoshino K., et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3:196–200. doi: 10.1038/ni758. [PubMed] [Cross Ref]
[143] Kim S.J., Park G.H., Kim D., Lee J., Min H., Wall E., et al. Analysis of cellular and behavioral responses to imiquimod reveals a unique itch pathway in transient receptor potential vanilloid 1 (TRPV1)-expressing neurons. Proc Natl Acad Sci U S A. 2011;108:3371–3376. doi: 10.1073/pnas.1019755108. [PubMed] [Cross Ref]
[144] Schon M.P., Schon M., Klotz K.N. The small antitumoral immune response modifier imiquimod interacts with adenosine receptor signaling in a TLR7- and TLR8-independent fashion. J Invest Dermatol. 2006;126:1338–1347. doi: 10.1038/sj.jid.5700286. [PubMed] [Cross Ref]
[145] Kaufman E.H., Fryer A.D., Jacoby D.B. Toll-like receptor 7 agonists are potent and rapid bronchodilators in guinea pigs. J Allergy Clin Immunol. 2011;127:462–469. doi: 10.1016/j.jaci.2010.10.029. [PMC free article] [PubMed] [Cross Ref]
[146] Lai Y., Gallo R.L. Toll-like receptors in skin infections and inflammatory diseases. Infect Disord Drug Targets. 2008;8:144–155. [PMC free article] [PubMed]
[147] Miller L.S. Toll-like receptors in skin. Adv Dermatol. 2008;24:71–87. doi: 10.1016/j.yadr.2008.09.004. [PMC free article] [PubMed] [Cross Ref]
[148] Meyer T., Stockfleth E., Christophers E. Immune response profiles in human skin. Br J Dermatol. 2007;157(Suppl2):1–7. doi: 10.1111/j.1365-2133.2007.08264.x. [PubMed] [Cross Ref]
[149] Chen J. History of pain theories. Neurosci Bull. 2011;27:343–350. doi: 10.1007/s12264-011-0139-0. [PMC free article] [PubMed] [Cross Ref]
[150] Kini S.P., Delong L.K., Veledar E., McKenzie-Brown A.M., Schaufele M., Chen S.C. The impact of pruritus on quality of life: The skin equivalent of pain. Arch Dermatol. 2011;147:1153–1156. doi: 10.1001/archdermatol.2011.178. [PubMed] [Cross Ref]
[151] Liu Q., Tang Z., Surdenikova L., Kim S., Patel K.N., Kim A., et al. Sensory neuron-specific GPCR Mrgprs are itch receptors mediating chloroquine-induced pruritus. Cell. 2009;139:1353–1365. doi: 10.1016/j.cell.2009.11.034. [PMC free article] [PubMed] [Cross Ref]

Articles from Neuroscience Bulletin are provided here courtesy of Springer