Intrathecal Administration of an Anti-nociceptive Non-CpG Oligodeoxynucleotide Reduces Glial Activation and Central Sensitization.
Complete Freund's adjuvant
IMT504
Inflammatory
Intrathecal administration
NFκB
Spinal cord
Journal
Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology
ISSN: 1557-1904
Titre abrégé: J Neuroimmune Pharmacol
Pays: United States
ID NLM: 101256586
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
02
09
2020
accepted:
12
01
2021
pubmed:
28
1
2021
medline:
29
1
2022
entrez:
27
1
2021
Statut:
ppublish
Résumé
Inflammatory pain associates with spinal glial activation and central sensitization. Systemic administration of IMT504, a non-CpG oligodeoxynucleotide originally designed as an immunomodulator, exerts remarkable anti-allodynic effects in rats with complete Freund´s adjuvant (CFA)-induced hindpaw inflammation. However, the anti-nociceptive mechanisms of IMT504 remain unknown. Here we evaluated whether IMT504 blocks inflammatory pain-like behavior by modulation of spinal glia and central sensitization. The study was performed in Sprague Dawley rats with intraplantar CFA, and a single lumbosacral intrathecal (i.t.) administration of IMT504 or vehicle was chosen to address if changes in glial activation and spinal sensitization relate to the pain-like behavior reducing effects of the ODN. Naïve rats were also included. Von Frey and Randall-Selitto tests, respectively, exposed significant reductions in allodynia and mechanical hypersensitivity, lasting at least 24 h after i.t. IMT504. Analysis of electromyographic responses to electrical stimulation of C fibers showed progressive reductions in wind-up responses. Accordingly, IMT504 significantly downregulated spinal glial activation, as shown by reductions in the protein expression of glial fibrillary acidic protein, CD11b/c, Toll-like receptor 4 (TLR4) and the phosphorylated p65 subunit of NFκB, evaluated by immunohistochemistry and western blot. In vitro experiments using early post-natal cortical glial cultures provided further support to in vivo data and demonstrated IMT504 internalization into microglia and astrocytes. Altogether, our study provides new evidence on the central mechanisms of anti-nociception by IMT504 upon intrathecal application, and further supports its value as a novel anti-inflammatory ODN with actions upon glial cells and the TLR4/NFκB pathway. Intrathecal administration of the non-CpG ODN IMT504 fully blocks CFA-induced mechanical allodynia and hypersensitivity, in association with reduced spinal sensitization. Administration of the ODN also results in downregulated gliosis and reduced TLR4-NF-κB pathway activation. IMT504 uptake into astrocytes and microglia support the concept of direct modulation of CFA-induced glial activation.
Identifiants
pubmed: 33502706
doi: 10.1007/s11481-021-09983-6
pii: 10.1007/s11481-021-09983-6
doi:
Substances chimiques
Oligodeoxyribonucleotides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
818-834Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.
Références
Ahmed AS, Li J, Ahmed M et al (2010) Attenuation of pain and inflammation in adjuvant-induced arthritis by the proteasome inhibitor MG132. Arthritis Rheum 62:2160–2169. https://doi.org/10.1002/art.27492
doi: 10.1002/art.27492
pubmed: 20506183
Alvarez P, Hernández A, Constandil L et al (2014) Stage-dependent C-reflex, pain-like behavior and opioid analgesia during the induction of chronic arthritis in rats. Eur J Neurosci 40:3264–3272. https://doi.org/10.1111/ejn.12685
doi: 10.1111/ejn.12685
pubmed: 25145673
Auzmendi J, Moffatt L, Ramos AJ (2020) Predicting reactive astrogliosis propagation by Bayesian computational modeling: the repeater stations model. Mol Neurobiol 57:879–895. https://doi.org/10.1007/s12035-019-01749-9
doi: 10.1007/s12035-019-01749-9
pubmed: 31522382
Ayoub AE, Salm AK (2003) Increased morphological diversity of microglia in the activated hypothalamic supraoptic nucleus. J Neurosci 23:7759–7766. https://doi.org/10.1523/jneurosci.23-21-07759.2003
doi: 10.1523/jneurosci.23-21-07759.2003
pubmed: 12944504
pmcid: 6740605
Basbaum AI, Bautista DM, Scherrer G, Julius D (2009) Cellular and molecular mechanisms of pain. Cell 139:267–284. https://doi.org/10.1016/j.cell.2009.09.028
doi: 10.1016/j.cell.2009.09.028
pubmed: 19837031
pmcid: 2852643
Bauer S, Kirschning CJ, Häcker H et al (2001) Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A 98:9237–9242. https://doi.org/10.1073/pnas.161293498
doi: 10.1073/pnas.161293498
pubmed: 11470918
pmcid: 55404
Beart PM, O’Shea RD (2007) Transporters for L-glutamate: an update on their molecular pharmacology and pathological involvement. Br J Pharmacol 150:5–17. https://doi.org/10.1038/sj.bjp.0706949
doi: 10.1038/sj.bjp.0706949
pubmed: 17088867
Ben HL, Carrillo-de Sauvage MA, Ceyzériat K, Escartin C (2015) Elusive roles for reactive astrocytes in neurodegenerative diseases. Front Cell Neurosci 9:1–27. https://doi.org/10.3389/fncel.2015.00278
doi: 10.3389/fncel.2015.00278
Bruno K, Woller SA, Miller YI et al (2018) Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states. Pain 159:1908–1915. https://doi.org/10.1097/j.pain.0000000000001306
doi: 10.1097/j.pain.0000000000001306
pubmed: 29889119
pmcid: 7890571
Chahin A, Opal SM, Zorzopulos J et al (2015) The novel immunotherapeutic oligodeoxynucleotide imt504 protects neutropenic animals from fatal pseudomonas aeruginosa bacteremia and sepsis. Antimicrob Agents Chemother 59:1225–1229. https://doi.org/10.1128/AAC.03923-14
doi: 10.1128/AAC.03923-14
pubmed: 25512413
pmcid: 4335857
Chaplan SR, Bach FW, Pogrel JW et al (1994) Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 53:55–63. https://doi.org/10.1016/0165-0270(94)90144-9
doi: 10.1016/0165-0270(94)90144-9
pubmed: 7990513
Coronel MF, Hernando-Insúa A, Rodriguez JM et al (2008) Oligonucleotide IMT504 reduces neuropathic pain after peripheral nerve injury. Neurosci Lett 444:69–73. https://doi.org/10.1016/j.neulet.2008.07.045
doi: 10.1016/j.neulet.2008.07.045
pubmed: 18672022
Costigan M, Moss A, Latremoliere A et al (2009) T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci 29:14415–14422. https://doi.org/10.1523/JNEUROSCI.4569-09.2009
doi: 10.1523/JNEUROSCI.4569-09.2009
pubmed: 19923276
pmcid: 2813708
Doyle SL, O’Neill LAJ (2006) Toll-like receptors: From the discovery of NFκB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol 72:1102–1113. https://doi.org/10.1016/j.bcp.2006.07.010
doi: 10.1016/j.bcp.2006.07.010
pubmed: 16930560
Elias F, Flo J, Lopez RA et al (2003) Strong cytosine-guanosine-independent immunostimulation in humans and other primates by synthetic oligodeoxynucleotides with PyNTTTTGT motifs. J Immunol 171:3697–3704. https://doi.org/10.4049/jimmunol.171.7.3697
doi: 10.4049/jimmunol.171.7.3697
pubmed: 14500668
Elias F, Flo J, Rodriguez JM et al (2005) PyNTTTTGT prototype oligonucleotide IMT504 is a potent adjuvant for the recombinant Hepatitis B vaccine that enhances the Th1 response. Vaccine 23:3597–3603. https://doi.org/10.1016/j.vaccine.2004.12.030
doi: 10.1016/j.vaccine.2004.12.030
pubmed: 15855019
Franco R, Rodriguez JM, Elías F et al (2014) Non-clinical safety studies of IMT504, a unique non-CpG oligonucleotide. Nucleic Acid Ther 24:267–282. https://doi.org/10.1089/nat.2013.0479
doi: 10.1089/nat.2013.0479
pubmed: 24720569
pmcid: 4106379
Fu ES, Zhang YP, Sagen J et al (2007) Transgenic glial nuclear factor-kappa B inhibition decreases formalin pain in mice. Neuroreport 18:713–717. https://doi.org/10.1097/WNR.0b013e3280d9e869
doi: 10.1097/WNR.0b013e3280d9e869
pubmed: 17426605
Gao YJ, Ji RR (2010a) Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther 126:56–68. https://doi.org/10.1016/j.pharmthera.2010.01.002
doi: 10.1016/j.pharmthera.2010.01.002
pubmed: 20117131
pmcid: 2839017
Gao YJ, Ji RR (2010b) Targeting astrocyte signaling for chronic pain. Neurotherapeutics 7:482–493. https://doi.org/10.1016/j.nurt.2010.05.016
doi: 10.1016/j.nurt.2010.05.016
pubmed: 20880510
pmcid: 2950097
Gao YJ, Xu ZZ, Liu YC et al (2010) 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. https://doi.org/10.1016/j.pain.2009.11.017
doi: 10.1016/j.pain.2009.11.017
pubmed: 20022176
pmcid: 2814908
Geary RS, Norris D, Yu R, Bennett CF (2015) Pharmacokinetics, biodistribution and cell uptake of antisense oligonucleotides. Adv Drug Deliv Rev 87:46–51. https://doi.org/10.1016/j.addr.2015.01.008
doi: 10.1016/j.addr.2015.01.008
pubmed: 25666165
Guo W, Wang H, Watanabe M et al (2007) Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27:6006–6018. https://doi.org/10.1523/JNEUROSCI.0176-07.2007
doi: 10.1523/JNEUROSCI.0176-07.2007
pubmed: 17537972
pmcid: 2676443
Hernando-Insúa A, Montaner AD, Rodriguez JM et al (2007) IMT504, the prototype of the immunostimulatory oligonucleotides of the PyNTTTTGT class, increases the number of progenitors of mesenchymal stem cells both in vitro and in vivo: potential use in tissue repair therapy. Stem Cells 25:1047–1054. https://doi.org/10.1634/stemcells.2006-0479
doi: 10.1634/stemcells.2006-0479
pubmed: 17420228
Hoffmann S, Beyer C (2020) A fatal alliance between microglia, inflammasomes, and central pain. Int J Mol Sci 21:1–13. https://doi.org/10.3390/ijms21113764
doi: 10.3390/ijms21113764
Huang YH, Bergles DE (2004) Glutamate transporters bring competition to the synapse. Curr Opin Neurobiol 14:346–352. https://doi.org/10.1016/j.conb.2004.05.007
doi: 10.1016/j.conb.2004.05.007
pubmed: 15194115
Jaeger LB, Banks WA (2005) Transport of antisense across the blood-brain barrier. Methods Mol Med 106:237–251. https://doi.org/10.1385/1-59259-854-4:237
doi: 10.1385/1-59259-854-4:237
pubmed: 15375320
Ji RR, Berta T, Nedergaard M (2013) Glia and pain: Is chronic pain a gliopathy? Pain 154:10–28. https://doi.org/10.1016/j.pain.2013.06.022
doi: 10.1016/j.pain.2013.06.022
Ji RR, Chamessian A, Zhang YQ (2016) Pain regulation by non-neuronal cells and inflammation. Science 354:572–577. https://doi.org/10.1126/science.aaf8924
doi: 10.1126/science.aaf8924
pubmed: 27811267
pmcid: 5488328
Ji RR, Nackley A, Huh Y et al (2018) Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology 129:343–366. https://doi.org/10.1097/ALN.0000000000002130
doi: 10.1097/ALN.0000000000002130
Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650. https://doi.org/10.1016/j.immuni.2011.05.006
doi: 10.1016/j.immuni.2011.05.006
pubmed: 21616434
Kayser V, Guilbaud G (1990) Differential effects of various doses of morphine and naloxone on two nociceptive test thresholds in arthritic and normal rats. Pain 41:353–363. https://doi.org/10.1016/0304-3959(90)90012-3
doi: 10.1016/0304-3959(90)90012-3
pubmed: 2388772
Keating A (2012) Mesenchymal stromal cells: New directions. Cell Stem Cell 10:709–716. https://doi.org/10.1016/j.stem.2012.05.015
doi: 10.1016/j.stem.2012.05.015
pubmed: 22704511
Krieg AM, Yi AK, Matson S et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549. https://doi.org/10.1038/374546a0
doi: 10.1038/374546a0
pubmed: 7700380
Krug A, Towarowski A, Britsch S, et al (2001) Toll-like receptor expression reveals CpG DNA as a unique microbial stimulus for plasmacytoid dendritic cells which synergizes with Cd40 ligand to induce high amounts of IL-12. Eur J Immunol 31:3026–3037. https://doi.org/10.1002/1521-4141(2001010)31:10<3026::AID-IMMU3026>3.0.CO;2-H
doi: 10.1002/1521-4141(2001010)31:10<3026::AID-IMMU3026>3.0.CO;2-H
pubmed: 11592079
Lacagnina MJ, Watkins LR, Grace PM (2018) Toll-like receptors and their role in persistent pain. Pharmacol Ther 184:145–158. https://doi.org/10.1016/j.pharmthera.2017.10.006
doi: 10.1016/j.pharmthera.2017.10.006
pubmed: 28987324
Le Blanc K, Mougiakakos D (2012) Multipotent mesenchymal stromal cells and the innate immune system. Nat Rev Immunol 12:383–396. https://doi.org/10.1038/nri3209
doi: 10.1038/nri3209
pubmed: 22531326
Ledeboer A, Gamanos M, Lai W et al (2005a) Involvement of spinal cord nuclear factor κB activation in rat models of proinflammatory cytokine-mediated pain facilitation. Eur J Neurosci 22:1977–1986. https://doi.org/10.1111/j.1460-9568.2005.04379.x
doi: 10.1111/j.1460-9568.2005.04379.x
pubmed: 16262636
Ledeboer A, Sloane EM, Milligan ED et al (2005b) Minocycline attenuates mechanical allodynia and proinflammatory cytokine expression in rat models of pain facilitation. Pain 115:71–83. https://doi.org/10.1016/j.pain.2005.02.009
doi: 10.1016/j.pain.2005.02.009
pubmed: 15836971
Lee K-M, Kang B-S, Lee H-L et al (2004) Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci 19:3375–3381. https://doi.org/10.1111/j.0953-816X.2004.03441.x
doi: 10.1111/j.0953-816X.2004.03441.x
pubmed: 15217394
Lehnardt S, Massillon L, Follett P et al (2003) Activation of innate immunity in the CNS triggers neurodegeneration through a Toll-like receptor 4-dependent pathway. Proc Natl Acad Sci U S A 100:8514–8519. https://doi.org/10.1073/pnas.1432609100
doi: 10.1073/pnas.1432609100
pubmed: 12824464
pmcid: 166260
Leiguarda C, Coronel MF, Montaner AD et al (2018) Long-lasting ameliorating effects of the oligodeoxynucleotide IMT504 on mechanical allodynia and hindpaw edema in rats with chronic hindpaw inflammation. Neurosci Lett 666:17–23. https://doi.org/10.1016/j.neulet.2017.12.032
doi: 10.1016/j.neulet.2017.12.032
pubmed: 29248616
Leiguarda C, Potilinski C, Rubione J et al (2020) IMT504 Provides analgesia by modulating cell infiltrate and inflammatory milieu in a chronic pain model. J Neuroimmune Pharmacol. https://doi.org/10.1007/s11481-020-09971-2
Li Y, Zhang H, Zhang H et al (2014) Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain 15:712–725. https://doi.org/10.1016/j.jpain.2014.04.001
doi: 10.1016/j.jpain.2014.04.001
pubmed: 24755282
pmcid: 4083500
Liu T, Gao YJ, Ji RR (2012) Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull 28:131–144. https://doi.org/10.1007/s12264-012-1219-5
doi: 10.1007/s12264-012-1219-5
pubmed: 22466124
pmcid: 3347759
Liu T, Han Q, Chen G et al (2016) Toll-like receptor 4 contributes to chronic itch, alloknesis, and spinal astrocyte activation in male mice. Pain 157:806–817. https://doi.org/10.1097/j.pain.0000000000000439
doi: 10.1097/j.pain.0000000000000439
pubmed: 26645545
pmcid: 4946956
Lu YC, Yeh WC, Ohashi PS (2008) LPS/TLR4 signal transduction pathway. Cytokine 42:145–151. https://doi.org/10.1016/j.cyto.2008.01.006
doi: 10.1016/j.cyto.2008.01.006
pubmed: 18304834
Luo JG, Zhao XL, Xu WC et al (2014) Activation of spinal NF-κB/p65 contributes to peripheral inflammation and hyperalgesia in rat adjuvant-induced arthritis. Arthritis Rheumatol 66:896–906. https://doi.org/10.1002/art.38328
doi: 10.1002/art.38328
pubmed: 24757142
Mapplebeck JCS, Beggs S, Salter MW (2016) Sex differences in pain: A tale of two immune cells. Pain 157:S2–S6. https://doi.org/10.1097/j.pain.0000000000000389
doi: 10.1097/j.pain.0000000000000389
pubmed: 26785152
Mazur C, Powers B, Zasadny K et al (2019) Brain pharmacology of intrathecal antisense oligonucleotides revealed through multimodal imaging. JCI Insight 4. https://doi.org/10.1172/jci.insight.129240
Mestre C, Pélissier T, Fialip J et al (1994) A method to perform direct transcutaneous intrathecal injection in rats. J Pharmacol Toxicol Methods 32:197–200. https://doi.org/10.1016/1056-8719(94)90087-6
doi: 10.1016/1056-8719(94)90087-6
pubmed: 7881133
Montaner AD, Denichilo A, Rodríguez JM et al (2011) Addition of the immunostimulatory oligonucleotide IMT504 to a seasonal flu vaccine increases hemagglutinin antibody titers in young adult and elder rats, and expands the anti-hemagglutinin antibody repertoire. Nucleic Acid Ther 21:265–274. https://doi.org/10.1089/nat.2011.0284
doi: 10.1089/nat.2011.0284
pubmed: 21793787
Möser CV, Möller M, Fleck SC et al (2019) Inhibition of the protein kinase IKKepsilon attenuates neuropathic pain in mice. Neuropharmacology 146:198–211. https://doi.org/10.1016/j.neuropharm.2018.12.004
doi: 10.1016/j.neuropharm.2018.12.004
pubmed: 30528326
Murta V, Schilrreff P, Rosciszewski G et al (2018) G5G2.5 core-shell tecto-dendrimer specifically targets reactive glia in brain ischemia. J Neurochem 144:748–760. https://doi.org/10.1111/jnc.14286
doi: 10.1111/jnc.14286
pubmed: 29280499
Niederberger E, Schmidtko A, Gao W et al (2007) Impaired acute and inflammatory nociception in mice lacking the p50 subunit of NF-κB. Eur J Pharmacol 559:55–60. https://doi.org/10.1016/j.ejphar.2006.11.074
doi: 10.1016/j.ejphar.2006.11.074
pubmed: 17217946
Piao Y, Gwon DH, Kang DW et al (2018) TLR4-mediated autophagic impairment contributes to neuropathic pain in chronic constriction injury mice. Mol Brain 11:1–11. https://doi.org/10.1186/s13041-018-0354-y
doi: 10.1186/s13041-018-0354-y
Prockop DJ, Oh JY (2012) Medical therapies with adult stem/progenitor cells (MSCs): A backward journey from dramatic results in vivo to the cellular and molecular explanations. J Cell Biochem 113:1460–1469. https://doi.org/10.1002/jcb.24046
doi: 10.1002/jcb.24046
pubmed: 22213121
pmcid: 4147853
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. https://doi.org/10.1111/j.1460-9568.2004.03514.x
doi: 10.1111/j.1460-9568.2004.03514.x
pubmed: 15233755
Randall LO, Selitto JJ (1957) A method for measurement of analgesic activity on inflamed tissue. Arch Int Pharmacodyn Ther 111:409–419
pubmed: 13471093
Rodriguez JM, Elías F, Fló J et al (2006) Immunostimulatory PyNTTTTGT oligodeoxynucleotides: Structural properties and refinement of the active motif. Oligonucleotides 16:275–285. https://doi.org/10.1089/oli.2006.16.275
doi: 10.1089/oli.2006.16.275
pubmed: 16978090
Rodriguez JM, Marchicio J, López M et al (2015) PyNTTTTGT and CpG immunostimulatory oligonucleotides: Effect on Granulocyte/Monocyte Colony-Stimulating Factor (GM-CSF) secretion by human CD56+ (NK and NKT) cells. PLoS One 10:1–20. https://doi.org/10.1371/journal.pone.0117484
doi: 10.1371/journal.pone.0117484
Rosciszewski G, Cadena V, Murta V et al (2018) Toll-like receptor 4 (TLR4) and Triggering Receptor Expressed on Myeloid Cells-2 (TREM-2) activation balance astrocyte polarization into a proinflammatory phenotype. Mol Neurobiol 55:3875–3888. https://doi.org/10.1007/s12035-017-0618-z
doi: 10.1007/s12035-017-0618-z
pubmed: 28547529
Rosciszewski G, Cadena V, Auzmendi J et al (2019) Detrimental effects of HMGB-1 require microglial-astroglial interaction: implications for the status epilepticus -induced neuroinflammation. Front Cell Neurosci 13:1–19. https://doi.org/10.3389/fncel.2019.00380
doi: 10.3389/fncel.2019.00380
Saito O, Svensson CI, Buczynski MW et al (2010) Spinal glial TLR4-mediated nociception and production of prostaglandin E(2) and TNF. Br J Pharmacol 160:1754–1764. https://doi.org/10.1111/j.1476-5381.2010.00811.x
doi: 10.1111/j.1476-5381.2010.00811.x
pubmed: 20649577
pmcid: 2936846
Sorge RE, LaCroix-Fralish ML, Tuttle AH et al (2011) Spinal cord toll-like receptor 4 mediates inflammatory and neuropathic hypersensitivity in male but not female mice. J Neurosci 31:15450–15454. https://doi.org/10.1523/JNEUROSCI.3859-11.2011
doi: 10.1523/JNEUROSCI.3859-11.2011
pubmed: 22031891
pmcid: 3218430
Strimbu-Gozariu M, Guirimand F, Willer JC, Le Bars D (1993) A sensitive test for studying the effects of opioids on a C-fibre reflex elicited by a wide range of stimulus intensities in the rat. Eur J Pharmacol 237:197–205. https://doi.org/10.1016/0014-2999(93)90269-N
doi: 10.1016/0014-2999(93)90269-N
pubmed: 8396036
Sun X, Zhang H (2018) miR-451 elevation relieves inflammatory pain by suppressing microglial activation-evoked inflammatory response via targeting TLR4. Cell Tissue Res 374:487–495. https://doi.org/10.1007/s00441-018-2898-7
doi: 10.1007/s00441-018-2898-7
pubmed: 30069596
Suter MR (2016) Microglial role in the development of chronic pain. Curr Opin Anaesthesiol 29:584–589. https://doi.org/10.1097/ACO.0000000000000373
doi: 10.1097/ACO.0000000000000373
pubmed: 27496572
Takeda K, Akira S (2004) TLR signaling pathways. Semin Immunol 16:3–9. https://doi.org/10.1016/j.smim.2003.10.003
doi: 10.1016/j.smim.2003.10.003
pubmed: 14751757
Vaure C, Liu Y (2014) A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front Immunol 5:1–15. https://doi.org/10.3389/fimmu.2014.00316
doi: 10.3389/fimmu.2014.00316
Villarreal A, Seoane R, Torres AG et al (2014) S100B protein activates a RAGE-dependent autocrine loop in astrocytes: Implications for its role in the propagation of reactive gliosis. J Neurochem 131:190–205. https://doi.org/10.1111/jnc.12790
doi: 10.1111/jnc.12790
pubmed: 24923428
Vlaeyen JWS, Maher CG, Wiech K et al (2018) Low back pain. Nat Rev Dis Prim 4:53–63. https://doi.org/10.1038/s41572-018-0052-1
doi: 10.1038/s41572-018-0052-1
Wolf DA, Hesterman JY, Sullivan JM et al (2016) Dynamic dual-isotope molecular imaging elucidates principles for optimizing intrathecal drug delivery. JCI Insight 1. https://doi.org/10.1172/jci.insight.85311
Zhao G, Jin H, Li J et al (2009) PyNTTTTGT prototype oligonucleotide IMT504, a novel effective adjuvant of the FMDV DNA vaccine. Viral Immunol 22:131–138. https://doi.org/10.1089/vim.2008.0073
doi: 10.1089/vim.2008.0073
pubmed: 19327000
Zhao LX, Jiang BC, Wu XB et al (2014) Ligustilide attenuates inflammatory pain via inhibition of NFκB-mediated chemokines production in spinal astrocytes. Eur J Neurosci 39:1391–1402. https://doi.org/10.1111/ejn.12502
doi: 10.1111/ejn.12502
pubmed: 24521480
Zhao XH, Zhang T, Li YQ (2015) The up-regulation of spinal Toll-like receptor 4 in rats with inflammatory pain induced by complete Freund’s adjuvant. Brain Res Bull 111:97–103. https://doi.org/10.1016/j.brainresbull.2015.01.002
doi: 10.1016/j.brainresbull.2015.01.002
pubmed: 25592618
Zhou YL, Zhou SZ, Li HL et al (2018) Bidirectional modulation between infiltrating CD3 + T-lymphocytes and astrocytes in the spinal cord drives the development of allodynia in monoarthritic rats. Sci Rep. https://doi.org/10.1038/s41598-017-18357-z
doi: 10.1038/s41598-017-18357-z
pubmed: 30560901
pmcid: 6298988
Zucoloto AZ, Manchope MF, Borghi SM et al (2019) Probucol ameliorates complete Freund’s adjuvant-induced hyperalgesia by targeting peripheral and spinal cord inflammation. Inflammation 42:1474–1490. https://doi.org/10.1007/s10753-019-01011-3
doi: 10.1007/s10753-019-01011-3
pubmed: 31011926