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Neuropathic Pain

The Role of Neuroinflammation in Complex Regional Pain Syndrome: A Comprehensive Review

ORCID Icon, , , &
Pages 3061-3073 | Received 16 Jun 2023, Accepted 26 Aug 2023, Published online: 06 Sep 2023

References

  • Nicholas M, Vlaeyen JWS, Rief W, et al. The IASP classification of chronic pain for ICD-11: chronic primary pain. Pain. 2019;160(1):28–37. doi:10.1097/j.pain.0000000000001390
  • Harden RN, McCabe CS, Goebel A, et al. Complex regional pain syndrome: practical diagnostic and treatment guidelines. Pain Med. 2022;23(Suppl 1):S1–s53. doi:10.1093/pm/pnac046
  • David Clark J, Tawfik VL, Tajerian M, Kingery WS. Autoinflammatory and autoimmune contributions to complex regional pain syndrome. Mol Pain. 2018;14:1744806918799127. doi:10.1177/1744806918799127
  • Birklein F, Ajit SK, Goebel A, Perez R, Sommer C. Complex regional pain syndrome - phenotypic characteristics and potential biomarkers. Nat Rev Neurol. 2018;14(5):272–284. doi:10.1038/nrneurol.2018.20
  • Elsamadicy AA, Yang S, Sergesketter AR, et al. Prevalence and cost analysis of complex regional pain syndrome (CRPS): a role for neuromodulation. Neuromodulation. 2018;21(5):423–430. doi:10.1111/ner.12691
  • Ayyaswamy B, Saeed B, Anand A, Chan L, Shetty V. Quality of life after amputation in patients with advanced complex regional pain syndrome: a systematic review. EFORT Open Rev. 2019;4(9):533–540. doi:10.1302/2058-5241.4.190008
  • Kessler A, Yoo M, Calisoff R. Complex regional pain syndrome: an updated comprehensive review. NeuroRehabilitation. 2020;47(3):253–264. doi:10.3233/nre-208001
  • Shim H, Rose J, Halle S, Shekane P. Complex regional pain syndrome: a narrative review for the practising clinician. Br J Anaesth. 2019;123(2):e424–e433. doi:10.1016/j.bja.2019.03.030
  • Baronio M, Sadia H, Paolacci S, et al. Molecular aspects of regional pain syndrome. Pain Res Manag. 2020;2020:7697214. doi:10.1155/2020/7697214
  • Ji RR, Xu ZZ, Gao YJ. Emerging targets in neuroinflammation-driven chronic pain. Nat Rev Drug Discov. 2014;13(7):533–548. doi:10.1038/nrd4334
  • Matsuda M, Huh Y, Ji RR. Roles of inflammation, neurogenic inflammation, and neuroinflammation in pain. J Anesth. 2019;33(1):131–139. doi:10.1007/s00540-018-2579-4
  • Ji RR, Nackley A, Huh Y, Terrando N, Maixner W. Neuroinflammation and central sensitization in chronic and widespread pain. Anesthesiology. 2018;129(2):343–366. doi:10.1097/aln.0000000000002130
  • Pinho-Ribeiro FA, Verri WA, Chiu IM. Nociceptor sensory neuron–immune interactions in pain and inflammation. Trends Immunol. 2017;38(1):5–19. doi:10.1016/j.it.2016.10.001
  • Ellis A, Bennett DL. Neuroinflammation and the generation of neuropathic pain. Br J Anaesth. 2013;111(1):26–37. doi:10.1093/bja/aet128
  • Huh Y, Ji RR, Chen G. Neuroinflammation, bone marrow stem cells, and chronic pain. Front Immunol. 2017;8:1014. doi:10.3389/fimmu.2017.01014
  • Gao YJ, Ji RR. Chemokines, neuronal-glial interactions, and central processing of neuropathic pain. Pharmacol Ther. 2010;126(1):56–68. doi:10.1016/j.pharmthera.2010.01.002
  • Kawasaki Y, Zhang L, Cheng JK, Ji RR. 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(20):5189–5194. doi:10.1523/jneurosci.3338-07.2008
  • Seo S, Jung YH, Lee D, et al. Abnormal neuroinflammation in fibromyalgia and CRPS using [11C]-(R)-PK11195 PET. PLoS One. 2021;16(2):e0246152. doi:10.1371/journal.pone.0246152
  • Zhang Y, Chen R, Hu Q, et al. Electroacupuncture ameliorates mechanical allodynia of a rat model of CRPS-I via Suppressing NLRP3 inflammasome activation in spinal cord dorsal horn neurons. Front Cell Neurosci. 2022;16:826777. doi:10.3389/fncel.2022.826777
  • Jung YH, Kim H, Jeon SY, et al. Brain metabolites and peripheral biomarkers associated with neuroinflammation in complex regional pain syndrome using [11C]-(R)-PK11195 positron emission tomography and magnetic resonance spectroscopy: a pilot study. Pain Med. 2019;20(3):504–514. doi:10.1093/pm/pny111
  • Chiu IM, von Hehn CA, Woolf CJ. Neurogenic inflammation and the peripheral nervous system in host defense and immunopathology. Nat Neurosci. 2012;15(8):1063–1067. doi:10.1038/nn.3144
  • Xanthos DN, Sandkühler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15(1):43–53. doi:10.1038/nrn3617
  • Torii H, Hosoi J, Beissert S, et al. Regulation of cytokine expression in macrophages and the Langerhans cell-like line XS52 by calcitonin gene-related peptide. J Leukoc Biol. 1997;61(2):216–223. doi:10.1002/jlb.61.2.216
  • Szolcsányi J. Capsaicin-sensitive sensory nerve terminals with local and systemic efferent functions: facts and scopes of an unorthodox neuroregulatory mechanism. Prog Brain Res. 1996;113:343–359. doi:10.1016/s0079-6123(08)61097-3
  • Littlejohn G. Neurogenic neuroinflammation in fibromyalgia and complex regional pain syndrome. Nat Rev Rheumatol. 2015;11(11):639–648. doi:10.1038/nrrheum.2015.100
  • Gonzalez HL, Carmichael N, Dostrovsky JO, Charlton MP. Evaluation of the time course of plasma extravasation in the skin by digital image analysis. J Pain. 2005;6(10):681–688. doi:10.1016/j.jpain.2005.06.004
  • Coderre TJ, Bennett GJ. A hypothesis for the cause of complex regional pain syndrome-type I (reflex sympathetic dystrophy): pain due to deep-tissue microvascular pathology. Pain Med. 2010;11(8):1224–1238. doi:10.1111/j.1526-4637.2010.00911.x
  • Birklein F, Drummond PD, Li W, et al. Activation of cutaneous immune responses in complex regional pain syndrome. J Pain. 2014;15(5):485–495. doi:10.1016/j.jpain.2014.01.490
  • Birklein F, Schmelz M. Neuropeptides, neurogenic inflammation and complex regional pain syndrome (CRPS). Neurosci Lett. 2008;437(3):199–202. doi:10.1016/j.neulet.2008.03.081
  • Lewis GN, Rice DA, McNair PJ. Conditioned pain modulation in populations with chronic pain: a systematic review and meta-analysis. J Pain. 2012;13(10):936–944. doi:10.1016/j.jpain.2012.07.005
  • Holzer P. Neurogenic vasodilatation and plasma leakage in the skin. Gen Pharmacol. 1998;30(1):5–11. doi:10.1016/s0306-3623(97)00078-5
  • Veldman PH, Reynen HM, Arntz IE, Goris RJ. Signs and symptoms of reflex sympathetic dystrophy: prospective study of 829 patients. Lancet. 1993;342(8878):1012–1016. doi:10.1016/0140-6736(93)92877-v
  • Shi X, Guo TZ, Li W, et al. Exercise reverses nociceptive sensitization, upregulated neuropeptide signaling, inflammatory changes, anxiety, and memory impairment in a mouse tibia fracture model. Anesthesiology. 2018;129(3):557–575. doi:10.1097/aln.0000000000002332
  • Weber M, Birklein F, Neundörfer B, Schmelz M. Facilitated neurogenic inflammation in complex regional pain syndrome. Pain. 2001;91(3):251–257. doi:10.1016/s0304-3959(00)00445-0
  • Birklein F, Schmelz M, Schifter S, Weber M. The important role of neuropeptides in complex regional pain syndrome. Neurology. 2001;57(12):2179–2184. doi:10.1212/wnl.57.12.2179
  • Wei T, Li WW, Guo TZ, et al. Post-junctional facilitation of Substance P signaling in a tibia fracture rat model of complex regional pain syndrome type I. Pain. 2009;144(3):278–286. doi:10.1016/j.pain.2009.04.020
  • Bruehl S, Warner DS. An update on the pathophysiology of complex regional pain syndrome. Anesthesiology. 2010;113(3):713–725. doi:10.1097/ALN.0b013e3181e3db38
  • Marinus J, Moseley GL, Birklein F, et al. Clinical features and pathophysiology of complex regional pain syndrome. Lancet Neurol. 2011;10(7):637–648. doi:10.1016/s1474-4422(11)70106-5
  • Li WW, Guo TZ, Shi X, et al. Neuropeptide regulation of adaptive immunity in the tibia fracture model of complex regional pain syndrome. J Neuroinflammation. 2018;15(1):105. doi:10.1186/s12974-018-1145-1
  • Schlereth T, Dittmar JO, Seewald B, Birklein F. Peripheral amplification of sweating--a role for calcitonin gene-related peptide. J Physiol. 2006;576(Pt 3):823–832. doi:10.1113/jphysiol.2006.116111
  • Hagner S, Haberberger RV, Overkamp D, Hoffmann R, Voigt KH, McGregor GP. Expression and distribution of calcitonin receptor-like receptor in human hairy skin. Peptides. 2002;23(1):109–116. doi:10.1016/s0196-9781(01)00586-1
  • Krämer HH, He L, Lu B, Birklein F, Sommer C. Increased pain and neurogenic inflammation in mice deficient of neutral endopeptidase. Neurobiol Dis. 2009;35(2):177–183. doi:10.1016/j.nbd.2008.11.002
  • Ota H, Arai T, Iwatsuki K, et al. Pathological mechanism of musculoskeletal manifestations associated with CRPS type II: an animal study. Pain. 2014;155(10):1976–1985. doi:10.1016/j.pain.2014.06.016
  • Guo TZ, Wei T, Shi X, et al. Neuropeptide deficient mice have attenuated nociceptive, vascular, and inflammatory changes in a tibia fracture model of complex regional pain syndrome. Mol Pain. 2012;8:85. doi:10.1186/1744-8069-8-85
  • Kingery WS, Davies MF, Clark JD. A substance P receptor (NK1) antagonist can reverse vascular and nociceptive abnormalities in a rat model of complex regional pain syndrome type II. Pain. 2003;104(1–2):75–84. doi:10.1016/s0304-3959(02)00467-0
  • de Mos M, Huygen F, Stricker CBH, Dieleman JP, Sturkenboom M. The association between ACE inhibitors and the complex regional pain syndrome: suggestions for a neuro-inflammatory pathogenesis of CRPS. Pain. 2009;142(3):218–224. doi:10.1016/j.pain.2008.12.032
  • König S, Engl C, Bayer M, et al. Substance P serum degradation in complex regional pain syndrome - another piece of the puzzle? J Pain. 2022;23(3):501–507. doi:10.1016/j.jpain.2021.10.005
  • Sommer C, Leinders M, Üçeyler N. Inflammation in the pathophysiology of neuropathic pain. Pain. 2018;159(3):595–602. doi:10.1097/j.pain.0000000000001122
  • Verri WA, Cunha TM, Parada CA, Poole S, Cunha FQ, Ferreira SH. Hypernociceptive role of cytokines and chemokines: targets for analgesic drug development? Pharmacol Ther. 2006;112(1):116–138. doi:10.1016/j.pharmthera.2006.04.001
  • König S, Schlereth T, Birklein F. Molecular signature of complex regional pain syndrome (CRPS) and its analysis. Expert Rev Proteomics. 2017;14(10):857–867. doi:10.1080/14789450.2017.1366859
  • Uçeyler N, Eberle T, Rolke R, Birklein F, Sommer C. Differential expression patterns of cytokines in complex regional pain syndrome. Pain. 2007;132(1–2):195–205. doi:10.1016/j.pain.2007.07.031
  • Alexander GM, van Rijn MA, van Hilten JJ, Perreault MJ, Schwartzman RJ. Changes in cerebrospinal fluid levels of pro-inflammatory cytokines in CRPS. Pain. 2005;116(3):213–219. doi:10.1016/j.pain.2005.04.013
  • Maihöfner C, Handwerker HO, Neundörfer B, Birklein F. Mechanical hyperalgesia in complex regional pain syndrome: a role for TNF-alpha? Neurology. 2005;65(2):311–313. doi:10.1212/01.wnl.0000168866.62086.8f
  • Alexander GM, Perreault MJ, Reichenberger ER, Schwartzman RJ. Changes in immune and glial markers in the CSF of patients with complex regional pain syndrome. Brain Behav Immun. 2007;21(5):668–676. doi:10.1016/j.bbi.2006.10.009
  • van den Berg C, de Bree PN, Huygen F, Tiemensma J. Glucocorticoid treatment in patients with complex regional pain syndrome: a systematic review. Eur J Pain. 2022;26(10):2009–2035. doi:10.1002/ejp.2025
  • Dirckx M, Stronks DL, van Bodegraven-Hof EA, Wesseldijk F, Groeneweg JG, Huygen FJ. Inflammation in cold complex regional pain syndrome. Acta Anaesthesiol Scand. 2015;59(6):733–739. doi:10.1111/aas.12465
  • Chae JS, Park H, Ahn SH, et al. The effect of super-repressor IkB-Loaded Exosomes (Exo-srIκBs) in chronic post-ischemia pain (CPIP) models. Pharmaceutics. 2023;15(2):553. doi:10.3390/pharmaceutics15020553
  • de Oliveira Galassi T, Fernandes PF, Salgado ASI, et al. Preventive supplementation of omega-3 reduces pain and pro-inflammatory cytokines in a mouse model of complex regional pain syndrome type I. Front Integr Neurosci. 2022;16:840249. doi:10.3389/fnint.2022.840249
  • Xu X, Tao X, Huang P, et al. N-methyl-d-aspartate receptor subunit 2B on keratinocyte mediates peripheral and central sensitization in chronic post-ischemic pain in male rats. Brain Behav Immun. 2020;87:579–590. doi:10.1016/j.bbi.2020.02.003
  • Li WW, Guo TZ, Liang D, et al. The NALP1 inflammasome controls cytokine production and nociception in a rat fracture model of complex regional pain syndrome. Pain. 2009;147(1–3):277–286. doi:10.1016/j.pain.2009.09.032
  • Chen R, Yin C, Fang J, Liu B. The NLRP3 inflammasome: an emerging therapeutic target for chronic pain. J Neuroinflammation. 2021;18(1):84. doi:10.1186/s12974-021-02131-0
  • Shi X, Wang L, Li X, Sahbaie P, Kingery WS, Clark JD. Neuropeptides contribute to peripheral nociceptive sensitization by regulating interleukin-1β production in keratinocytes. Anesth Analg. 2011;113(1):175–183. doi:10.1213/ANE.0b013e31821a0258
  • Chen R, Yin C, Hu Q, et al. Expression profiling of spinal cord dorsal horn in a rat model of complex regional pain syndrome type-I uncovers potential mechanisms mediating pain and neuroinflammation responses. J Neuroinflammation. 2020;17(1):162. doi:10.1186/s12974-020-01834-0
  • Wei XH, Yang T, Wu Q, et al. Peri-sciatic administration of recombinant rat IL-1β induces mechanical allodynia by activation of src-family kinases in spinal microglia in rats. Exp Neurol. 2012;234(2):389–397. doi:10.1016/j.expneurol.2012.01.001
  • Yan X, Li F, Maixner DW, et al. Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome. Glia. 2019;67(3):482–497. doi:10.1002/glia.23557
  • Wood JN, Boorman JP, Okuse K, Baker MD. Voltage-gated sodium channels and pain pathways. J Neurobiol. 2004;61(1):55–71. doi:10.1002/neu.20094
  • Shi X, Guo TZ, Wei T, Li WW, Clark DJ, Kingery WS. Facilitated spinal neuropeptide signaling and upregulated inflammatory mediator expression contribute to postfracture nociceptive sensitization. Pain. 2015;156(10):1852–1863. doi:10.1097/j.pain.0000000000000204
  • Guo TZ, Wei T, Li WW, Li XQ, Clark JD, Kingery WS. Immobilization contributes to exaggerated neuropeptide signaling, inflammatory changes, and nociceptive sensitization after fracture in rats. J Pain. 2014;15(10):1033–1045. doi:10.1016/j.jpain.2014.07.004
  • Wei T, Guo TZ, Li WW, Kingery WS, Clark JD. Acute versus chronic phase mechanisms in a rat model of CRPS. J Neuroinflammation. 2016;13:14. doi:10.1186/s12974-015-0472-8
  • Helyes Z, Tékus V, Szentes N, et al. Transfer of complex regional pain syndrome to mice via human autoantibodies is mediated by interleukin-1-induced mechanisms. Proc Natl Acad Sci U S A. 2019;116(26):13067–13076. doi:10.1073/pnas.1820168116
  • Dirckx M, Groeneweg G, Wesseldijk F, Stronks DL, Huygen FJ. Report of a preliminary discontinued double-blind, randomized, placebo-controlled trial of the anti-TNF-α chimeric monoclonal antibody infliximab in complex regional pain syndrome. Pain Pract. 2013;13(8):633–640. doi:10.1111/papr.12078
  • Andersson U, Tracey KJ. Reflex principles of immunological homeostasis. Annu Rev Immunol. 2012;30:313–335. doi:10.1146/annurev-immunol-020711-075015
  • R-R J, Chamessian A, Zhang Y-Q. Pain regulation by non-neuronal cells and inflammation. Science. 2016;354(6312):572–577. doi:10.1126/science.aaf8924
  • Dirckx M, Groeneweg G, van Daele PL, Stronks DL, Huygen FJ. Mast cells: a new target in the treatment of complex regional pain syndrome? Pain Pract. 2013;13(8):599–603. doi:10.1111/papr.12049
  • Huygen FJ, Ramdhani N, van Toorenenbergen A, Klein J, Zijlstra FJ. Mast cells are involved in inflammatory reactions during complex regional pain syndrome type 1. Immunol Lett. 2004;91(2–3):147–154. doi:10.1016/j.imlet.2003.11.013
  • Schlereth T, Birklein F. Mast cells: source of inflammation in complex regional pain syndrome? Anesthesiology. 2012;116(4):756–757. doi:10.1097/ALN.0b013e31824bb143
  • Oliveira SM, Drewes CC, Silva CR, et al. Involvement of mast cells in a mouse model of postoperative pain. Eur J Pharmacol. 2011;672(1–3):88–95. doi:10.1016/j.ejphar.2011.10.001
  • Li WW, Guo TZ, Liang DY, Sun Y, Kingery WS, Clark JD. Substance P signaling controls mast cell activation, degranulation, and nociceptive sensitization in a rat fracture model of complex regional pain syndrome. Anesthesiology. 2012;116(4):882–895. doi:10.1097/ALN.0b013e31824bb303
  • Morellini N, Finch PM, Goebel A, Drummond PD. Dermal nerve fibre and mast cell density, and proximity of mast cells to nerve fibres in the skin of patients with complex regional pain syndrome. Pain. 2018;159(10):2021–2029. doi:10.1097/j.pain.0000000000001304
  • Kobayashi Y, Kiguchi N, Fukazawa Y, Saika F, Maeda T, Kishioka S. Macrophage-T cell interactions mediate neuropathic pain through the glucocorticoid-induced tumor necrosis factor ligand system. J Biol Chem. 2015;290(20):12603–12613. doi:10.1074/jbc.M115.636506
  • Schuh CD, Pierre S, Weigert A, et al. Prostacyclin mediates neuropathic pain through interleukin 1β-expressing resident macrophages. Pain. 2014;155(3):545–555. doi:10.1016/j.pain.2013.12.006
  • Trevisan G, Benemei S, Materazzi S, et al. TRPA1 mediates trigeminal neuropathic pain in mice downstream of monocytes/macrophages and oxidative stress. Brain. 2016;139(Pt 5):1361–1377. doi:10.1093/brain/aww038
  • Old EA, Nadkarni S, Grist J, et al. Monocytes expressing CX3CR1 orchestrate the development of vincristine-induced pain. J Clin Invest. 2014;124(5):2023–2036. doi:10.1172/jci71389
  • Liu T, Gao YJ, Ji RR. Emerging role of Toll-like receptors in the control of pain and itch. Neurosci Bull. 2012;28(2):131–144. doi:10.1007/s12264-012-1219-5
  • Liu XJ, Zhang Y, Liu T, et al. Nociceptive neurons regulate innate and adaptive immunity and neuropathic pain through MyD88 adapter. Cell Res. 2014;24(11):1374–1377. doi:10.1038/cr.2014.106
  • Massier J, Eitner A, Segond von Banchet G, Schaible HG. Effects of differently activated rodent macrophages on sensory neurons: implications for arthritis pain. Arthritis Rheumatol. 2015;67(8):2263–2272. doi:10.1002/art.39134
  • Segond von Banchet G, Boettger MK, Fischer N, Gajda M, Bräuer R, Schaible H-G. Experimental arthritis causes tumor necrosis factor-α-dependent infiltration of macrophages into rat dorsal root ganglia which correlates with pain-related behavior. Pain. 2009;145(1):151–159. doi:10.1016/j.pain.2009.06.002
  • De Logu F, Prá SD D, de David Antoniazzi CT, et al. Macrophages and Schwann cell TRPA1 mediate chronic allodynia in a mouse model of complex regional pain syndrome type I. Brain Behav Immun. 2020;88:535–546. doi:10.1016/j.bbi.2020.04.037
  • Palmer MT, Weaver CT. Autoimmunity: increasing suspects in the CD4+ T cell lineup. Nat Immunol. 2010;11(1):36–40. doi:10.1038/ni.1802
  • Russo MA, Fiore NT, van Vreden C, et al. Expansion and activation of distinct central memory T lymphocyte subsets in complex regional pain syndrome. J Neuroinflammation. 2019;16(1):63. doi:10.1186/s12974-019-1449-9
  • Russo MA, Georgius P, Pires AS, et al. Novel immune biomarkers in complex regional pain syndrome. J Neuroimmunol. 2020;347:577330. doi:10.1016/j.jneuroim.2020.577330
  • Bharwani KD, Dik WA, Dirckx M, Huygen F. Highlighting the role of biomarkers of inflammation in the diagnosis and management of complex regional pain syndrome. Mol Diagn Ther. 2019;23(5):615–626. doi:10.1007/s40291-019-00417-x
  • Bharwani KD, Dirckx M, Stronks DL, Dik WA, Schreurs MWJ, Huygen F. Elevated plasma levels of sIL-2R in Complex regional pain syndrome: a pathogenic role for T-lymphocytes? Mediators Inflamm. 2017;2017:2764261. doi:10.1155/2017/2764261
  • Ji RR, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch. Nat Rev Neurosci. 2019;20(11):667–685. doi:10.1038/s41583-019-0218-1
  • Inoue K, Tsuda M. Microglia in neuropathic pain: cellular and molecular mechanisms and therapeutic potential. Nat Rev Neurosci. 2018;19(3):138–152. doi:10.1038/nrn.2018.2
  • Hanani M, Huang TY, Cherkas PS, Ledda M, Pannese E. Glial cell plasticity in sensory ganglia induced by nerve damage. Neuroscience. 2002;114(2):279–283. doi:10.1016/s0306-4522(02)00279-8
  • Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy? Pain. 2013;154(0 1):S10–s28. doi:10.1016/j.pain.2013.06.022
  • Kiguchi N, Kobayashi D, Saika F, Matsuzaki S, Kishioka S. Pharmacological regulation of neuropathic pain driven by inflammatory macrophages. Int J Mol Sci. 2017;18:11.
  • Tsuda M, Inoue K. Neuron-microglia interaction by purinergic signaling in neuropathic pain following neurodegeneration. Neuropharmacology. 2016;104:76–81. doi:10.1016/j.neuropharm.2015.08.042
  • Li WW, Guo TZ, Shi X, et al. Substance P spinal signaling induces glial activation and nociceptive sensitization after fracture. Neuroscience. 2015;310:73–90. doi:10.1016/j.neuroscience.2015.09.036
  • Linnman C, Becerra L, Borsook D. Inflaming the brain: CRPS a model disease to understand neuroimmune interactions in chronic pain. J Neuroimmune Pharmacol. 2013;8(3):547–563. doi:10.1007/s11481-012-9422-8
  • Banati RB. Neuropathological imaging: in vivo detection of glial activation as a measure of disease and adaptive change in the brain. Br Med Bull. 2003;65:121–131. doi:10.1093/bmb/65.1.121
  • Banati RB, Cagnin A, Brooks DJ, et al. Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury. Neuroreport. 2001;12(16):3439–3442. doi:10.1097/00001756-200111160-00012
  • Tang Y, Liu L, Xu D, et al. Interaction between astrocytic colony stimulating factor and its receptor on microglia mediates central sensitization and behavioral hypersensitivity in chronic post ischemic pain model. Brain Behav Immun. 2018;68:248–260. doi:10.1016/j.bbi.2017.10.023
  • Xu J, Tang Y, Xie M, et al. Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post-ischemic pain model of complex regional pain syndrome type I in rats. Eur J Neurosci. 2016;44(12):3046–3055. doi:10.1111/ejn.13414
  • Luo X, Tai WL, Sun L, et al. Crosstalk between astrocytic CXCL12 and microglial CXCR4 contributes to the development of neuropathic pain. Mol Pain. 2016;12:174480691663638. doi:10.1177/1744806916636385
  • 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(2):624–630. doi:10.1124/jpet.103.052407
  • 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(3):772–783. doi:10.1111/j.1471-4159.2006.03746.x
  • Katsura H, Obata K, Mizushima T, et al. Activation of Src-family kinases in spinal microglia contributes to mechanical hypersensitivity after nerve injury. J Neurosci. 2006;26(34):8680–8690. doi:10.1523/jneurosci.1771-06.2006
  • Del Valle L, Schwartzman RJ, Alexander G. Spinal cord histopathological alterations in a patient with longstanding complex regional pain syndrome. Brain Behav Immun. 2009;23(1):85–91. doi:10.1016/j.bbi.2008.08.004
  • Tsujikawa S, DeMeulenaere KE, Centeno MV, et al. Regulation of neuropathic pain by microglial Orai1 channels. Sci Adv. 2023;9(4):eade7002. doi:10.1126/sciadv.ade7002
  • Berta T, Park CK, Xu ZZ, et al. Extracellular caspase-6 drives murine inflammatory pain via microglial TNF-α secretion. J Clin Invest. 2014;124(3):1173–1186. doi:10.1172/jci72230
  • Chen G, Zhang YQ, Qadri YJ, Serhan CN, Ji RR. Microglia in pain: detrimental and protective roles in pathogenesis and resolution of pain. Neuron. 2018;100(6):1292–1311. doi:10.1016/j.neuron.2018.11.009
  • Butovsky O, Weiner HL. Microglial signatures and their role in health and disease. Nat Rev Neurosci. 2018;19(10):622–635. doi:10.1038/s41583-018-0057-5
  • Beggs S, Trang T, Salter MW. P2X4R+ microglia drive neuropathic pain. Nat Neurosci. 2012;15(8):1068–1073. doi:10.1038/nn.3155
  • Calvo M, Bennett DL. The mechanisms of microgliosis and pain following peripheral nerve injury. Exp Neurol. 2012;234(2):271–282. doi:10.1016/j.expneurol.2011.08.018
  • Zhang RX, Li A, Liu B, et al. IL-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of NMDA receptor NR-1 subunit in rats. Pain. 2008;135(3):232–239. doi:10.1016/j.pain.2007.05.023
  • Hu X, Du L, Liu S, et al. A TRPV4-dependent neuroimmune axis in the spinal cord promotes neuropathic pain. J Clin Invest. 2023;133(5). doi:10.1172/jci161507
  • Lu HJ, Gao YJ. Astrocytes in chronic pain: cellular and molecular mechanisms. Neurosci Bull. 2023;39(3):425–439. doi:10.1007/s12264-022-00961-3
  • Li T, Tang Z, Wei J, Zhou Z, Wang B. Unambiguous tracking technique based on combined correlation functions for sine BOC signals. J Navigation. 2019;72(1):140–154. doi:10.1017/S0373463318000498
  • Escartin C, Galea E, Lakatos A, et al. Reactive astrocyte nomenclature, definitions, and future directions. Nat Neurosci. 2021;24(3):312–325. doi:10.1038/s41593-020-00783-4
  • Miller SJ. Astrocyte heterogeneity in the adult central nervous system. Front Cell Neurosci. 2018;12:401. doi:10.3389/fncel.2018.00401
  • Liddelow SA, Guttenplan KA, Clarke LE, et al. Neurotoxic reactive astrocytes are induced by activated microglia. Nature. 2017;541(7638):481–487. doi:10.1038/nature21029
  • Zhu A, Cui H, Su W, Liu C, Yu X, Huang Y. C3aR in astrocytes mediates post-thoracotomy pain by inducing A1 astrocytes in male rats. Biochim Biophys Acta Mol Basis Dis. 2023;1869(5):166672. doi:10.1016/j.bbadis.2023.166672
  • Gao Y-J, R-R J. Targeting astrocyte signaling for chronic pain. Neurotherapeutics. 2010;7(4):482–493. doi:10.1016/j.nurt.2010.05.016
  • Imai S, Ikegami D, Yamashita A, et al. Epigenetic transcriptional activation of monocyte chemotactic protein 3 contributes to long-lasting neuropathic pain. Brain. 2013;136(Pt 3):828–843. doi:10.1093/brain/aws330
  • Gao YJ, Zhang L, Samad OA, et al. JNK-induced MCP-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci. 2009;29(13):4096–4108. doi:10.1523/jneurosci.3623-08.2009
  • Zhang ZJ, Cao DL, Zhang X, Ji RR, Gao YJ. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain. 2013;154(10):2185–2197. doi:10.1016/j.pain.2013.07.002
  • Cheng T, Xu Z, Ma X. The role of astrocytes in neuropathic pain. Front Mol Neurosci. 2022;15:1007889. doi:10.3389/fnmol.2022.1007889
  • Tian G, Luo X, Tang C, et al. Astrocyte contributes to pain development via MMP2-JNK1/2 signaling in a mouse model of complex regional pain syndrome. Life Sci. 2017;170:64–71. doi:10.1016/j.lfs.2016.11.030
  • Stucky CL, Mikesell AR. Cutaneous pain in disorders affecting peripheral nerves. Neurosci Lett. 2021;765:136233. doi:10.1016/j.neulet.2021.136233
  • Talagas M, Lebonvallet N, Berthod F, Misery L. Cutaneous nociception: role of keratinocytes. Exp Dermatol. 2019;28(12):1466–1469. doi:10.1111/exd.13975
  • Moehring F, Cowie AM, Menzel AD, et al. Keratinocytes mediate innocuous and noxious touch via ATP-P2X4 signaling. eLife. 2018;7:e31684. doi:10.7554/eLife.31684
  • Sadler KE, Moehring F, Stucky CL. Keratinocytes contribute to normal cold and heat sensation. eLife. 2020;9:e58625. doi:10.7554/eLife.58625
  • Moehring F, Halder P, Seal RP, Stucky CL. Uncovering the cells and circuits of touch in normal and pathological settings. Neuron. 2018;100(2):349–360. doi:10.1016/j.neuron.2018.10.019
  • Talagas M, Lebonvallet N, Leschiera R, et al. Keratinocytes communicate with sensory neurons via synaptic-like contacts. Ann Neurol. 2020;88(6):1205–1219. doi:10.1002/ana.25912
  • Hou Q, Barr T, Gee L, et al. Keratinocyte expression of calcitonin gene-related peptide β: implications for neuropathic and inflammatory pain mechanisms. Pain. 2011;152(9):2036–2051. doi:10.1016/j.pain.2011.04.033
  • Li WW, Guo TZ, Li XQ, Kingery WS, Clark DJ. Fracture induces keratinocyte activation, proliferation, and expression of pro-nociceptive inflammatory mediators. Pain. 2010;151(3):843–852. doi:10.1016/j.pain.2010.09.026
  • Cirillo N. The local neuropeptide system of keratinocytes. Biomedicines. 2021;9(12):1854. doi:10.3390/biomedicines9121854