Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2023; 69(1): 54-67

The Biology of Neuropathic Pain

P. A. Smith

    Neuroscience and Mental Health Institute and Department of Pharmacology, University of Alberta, Edmonton, Canada


Nerve injury or disease often leads to intractable neuropathic pain. Axons which are severed undergo Wallerian degeneration. This involves the activation of Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells and the release of inflammatory cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins and alter ion channel function. This evokes spontaneous activity in primary afferent neurons that is crucial for the onset and maintenance of pain. In addition, secondary mediators such as colony stimulating factor 1 are generated and released from primary afferent terminals. These promote release of tertiary mediators such as brain-derived neurotrophic factor and interleukin 1b from spinal microglia and astrocytes. Tertiary mediators facilitate the generation and transmission of nociceptive information by facilitating excitatory transmission and attenuating inhibitory transmission in the dorsal horn. Transfer of information between neurons and immune cells is bidirectional. Neurons directly control immune cell function in a process termed neurogenic neuroinflammation. Increased permeability of the blood-brain barrier allows access of immune cells to neurons in central pain pathways. This, together with neurogenic neuroinflammation, increases activity throughout the pain sensory system. This review provides an overview of processes involved in the generation and persistence of peripherally generated neuropathic pain. Attention is drawn to the idea that pain etiology is dependent on the nature of the injury and different processes operate in males compared to females.

Keywords: neurogenic neuroinflammation; allodynia; dorsal horn; dorsal root ganglia; central sensitization; neuropathy; nerve injury; neuroimmunology; brain-derived neurotrophic factor.


  1. Colloca L, Ludman T, Bouhassira D, Baron R, Dickenson AH, Yarnitsky D, Freeman R, Truini A, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002. CrossRef PubMed PubMedCentral
  2. Finnerup NB, Kuner R, Jensen TS. Neuropathic pain: from mechanisms to treatment. Physiol Rev. 2021;101:259-301. CrossRef PubMed
  3. Gormsen L, Rosenberg R, Bach FW, Jensen TS. Depression, anxiety, health-related quality of life and pain in patients with chronic fibromyalgia and neuropathic pain. Eur J Pain. 2010;14:127-8. CrossRef PubMed
  4. Scholz, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci. 2007;10:1361-8. CrossRef PubMed
  5. Finnerup NB, Attal N, Haroutounian S, McNicol E, Baron R, Dworkin RH, Gilron I, Haanpaa M, Hansson P, Jensen, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:162-73. CrossRef PubMed
  6. Alles SRA, Smith PA. The etiology and pharmacology of neuropathic pain. Pharmacol Rev. 2018;70:315-47. CrossRef PubMed
  7. Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain. 2000;87:149-58. CrossRef PubMed
  8. Leung L, Cahill CM. TNF-alpha and neuropathic pain--a review. J Neuroinflammat. 2010;7:27. CrossRef PubMed PubMedCentral
  9. Boakye PA, Tang SJ, Smith PA. Mediators of neuropathic pain; focus on spinal microglia, CSF-1, BDNF, CCL21, TNF-alpha, Wnt ligands, and interleukin 1-beta. Front Pain Res. 2021;2:41. CrossRef PubMed PubMedCentral
  10. Pezet S, McMahon SB. Neurotrophins: Mediators and modulators of pain. Ann Rev Neurosci. 2006;29:507-38. CrossRef PubMed
  11. White FA, Wilson NM. Chemokines as pain mediators and modulators. Curr Opin Anaesthesiol. 2008;21:580-5. CrossRef PubMed PubMedCentral
  12. Silva RL, Lopes AH, Guimaraes RM, Cunha TM. CXCL1/CXCR2 signaling in pathological pain: Role in peripheral and central sensitization. Neurobiol Dis. 2017;105:109-16. CrossRef PubMed
  13. Yu Y, Huang X, Di Y, Qu L, Fan N. Effect of CXCL12/ CXCR4 signaling on neuropathic pain after chronic compression of dorsal root ganglion. Sci Rep. 2017; 7:5707. CrossRef PubMed PubMedCentral
  14. Kaur G, Singh N, Jaggi AS. Mast cells in neuropathic pain: an increasing spectrum of their involvement in pathophysiology. Rev Neurosci. 2017;28:759-66. CrossRef PubMed
  15. Obara I, Telezhkin V, Alrashdi I, Chazot PL. Histamine, histamine receptors, and neuropathic pain relief. Br J Pharmacol. 2020;177:580-99. CrossRef PubMed PubMedCentral
  16. van Vliet AC, Lee J, van der Poel M, Mason MRJ, Noordermeer JN, Fradkin LG, et al. Coordinated changes in the expression of Wnt pathway genes following human and rat peripheral nerve injury PLoS One. 12021;16: e0249748. CrossRef PubMed PubMedCentral
  17. Gangadharan V, Zheng H, Taberner FJ, Landry J, Nees TA, Pistolic J, Agarwal N, Mannich D, et al.Neuropathic pain caused by miswiring and abnormal end organ targeting. Nature. 2022;606:137-45. CrossRef PubMed PubMedCentral
  18. McLachlan EM, Janig W, Michalis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature. 1993;363:543-6. CrossRef PubMed
  19. Xanthos DN, Pungel I, Wunderbaldinger G, Sandkuhler J. Effects of peripheral inflammation on the blood-spinal cord barrier. Mol Pain. 2012;8: 44. CrossRef PubMed PubMedCentral
  20. Moalem G, Tracey DJ. Immune and inflammatory mechanisms in neuropathic pain Brain Res Rev. 2006;51:240-64. CrossRef PubMed
  21. Noh MC, Mikler B, Joy T, Smith PA. Time course of inflammation in dorsal root ganglia correlates with differential reversibility of mechanical allodynia. Neuroscience. 2020;428:199-216. CrossRef PubMed
  22. Baskozos G, Dawes JM, Austin JS, Antunes-Martins A, McDermott L, et al. Comprehensive analysis of long noncoding RNA expression in dorsal root ganglion reveals cell-type specificity and dysregulation after nerve injury. Pain. 2019;160:463-85. CrossRef PubMed PubMedCentral
  23. Liu L, Xu D, Wang T, Zhang Y, Yang X, Wang X, Tang Y. Epigenetic reduction of miR-214-3p upregulates astrocytic colony-stimulating factor-1 and contributes to neuropathic pain induced by nerve injury. Pain. 2020;161: 96-108. CrossRef PubMed
  24. Zhang YU, Ye G, Zhao J, Chen Y, Kong L, Sheng C, Yuan L. Exosomes carried miR-181c-5p alleviates neuropathic pain in CCI rat models. An Acad Bras Cienc. 2022;94: e20210564. CrossRef PubMed
  25. Noh MC, Stemkowski PL, Smith PA. Long-term actions of interleukin-1beta on K(+), Na(+) and Ca(2+) channel currents in small, IB4-positive dorsal root ganglion neurons; possible relevance to the etiology of neuropathic pain. J Neuroimmunol. 2019;332:198-211. CrossRef PubMed
  26. Stemkowski PL, Smith PA. Long-term IL-1beta exposure causes subpopulation-dependent alterations in rat dorsal root ganglion neuron excitability. J Neurophysiol. 2012;107:1586-97. CrossRef PubMed
  27. Stemkowski PL, Noh MC, Chen Y, Smith PA. Increased excitability of medium-sized dorsal root ganglion neurons by prolonged interleukin-1beta exposure is K(+) channel dependent and reversible. J Physiol. 2015;593:3739-55. CrossRef PubMed PubMedCentral
  28. Binshtok AM, Wang H, Zimmermann K, Amaya F, Vardeh D, Shi L, et al., Nociceptors are interleukin-1{beta} sensors. J Neurosci. 2008;28:14062-73. CrossRef PubMed PubMedCentral
  29. Pitcher GM, Henry JL. Governing role of primary afferent drive in increased excitation of spinal nociceptive neurons in a model of sciatic neuropathy. Exp Neurol. 2008;214: 219-28. CrossRef PubMed PubMedCentral
  30. Vaso A, Adahan HM, Gjika A, Zahaj S, Zhurda T, Vyshka G, Devor M. Peripheral nervous system origin of phantom limb pain. Pain. 2014;155:1384-91. CrossRef PubMed
  31. Yatziv SL, Devor M. Suppression of neuropathic pain by selective silencing of dorsal root ganglion ectopia using nonblocking concentrations of lidocaine. Pain. 2019;160:2105-14. CrossRef PubMed
  32. Dib-Hajj SD, Yang Y, Black JA, Waxman SG. The Na(V)1.7 sodium channel: from molecule to man. Nat Rev Neurosci. 2013;14: 49-62. CrossRef PubMed
  33. Waxman SG, Zamponi GW. Regulating excitability of peripheral afferents: emerging ion channel targets. Nat Neurosci. 2014;17:153-63. CrossRef PubMed
  34. Noh M-CS, Kumar N, Bukhanova N, Chen Y, Stemkowski PL, Smith PA. The heart-rate-reducing agent, ivabradine, reduces mechanical allodynia in a rodent model of neuropathic pain. Eur J Pain. 2014;18:1139-47. CrossRef PubMed
  35. Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol. 2014;14: 217-31. CrossRef PubMed PubMedCentral
  36. Xanthos DN, Sandkuhler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to neuronal activity. Nat Rev Neurosci. 2014;15:43-53. CrossRef PubMed
  37. McMahon SB, La Russa F, Bennett DL. Crosstalk between the nociceptive and immune systems in host defence and disease. Nat Rev Neurosci. 2015;16:389-402. CrossRef PubMed
  38. Okubo M, Yamanaka H, Kobayashi K, Dai Y, Kanda H, Yagi H, Noguchi K. Macrophage-Colony stimulating factor derived from injured primary afferent induces proliferation of spinal microglia and neuropathic pain in rats. PLoS One. 2016;11:e0153375. CrossRef PubMed PubMedCentral
  39. Guan Z, Kuhn JA, Wang X, Colquitt B, Solorzano C, Vaman S, Guan AK, et al., Injured sensory neuron-derived CSF1 induces microglial proliferation and DAP12- dependent pain. Nat Neurosci. 2016;19:94-101. CrossRef PubMed PubMedCentral
  40. Malcangio M. Role of the immune system in neuropathic pain. Scand J Pain. 2020;20:33-7. CrossRef PubMed
  41. Dong J, Xu C, Xia R, Zhang Z. Upregulating miR-130a-5p relieves astrocyte over activation-induced neuropathic pain through targeting C-X-C motif chemokine receptor 12/C-X-C motif chemokine receptor 4 axis. NeuroReport. 2021;32:135-43. CrossRef PubMed
  42. Mapplebeck JC, Beggs S, Salter MW. Molecules in pain and sex: a developing story. Mol Brain. 2017;10:9. CrossRef PubMed PubMedCentral
  43. Sorge RE, Mapplebeck JC, Rosen S, Beggs S, Taves S, Alexander JK, et al., Different immune cells mediate mechanical pain hypersensitivity in male and female mice. Nat Neurosci. 2015;18:1081-3. CrossRef PubMed PubMedCentral
  44. Coull JA, Boudreau D, Bachand K, Prescott SA, Nault F, Sik A, de Koninck P, de Koninck Y. Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature. 2003;424: 938-42. CrossRef PubMed
  45. Balasubramanyan S, Stemkowski PL, Stebbing MJ, Smith PA. Sciatic chronic constriction injury produces cell-type specific changes in the electrophysiological properties of rat Substantia Gelatinosa neurons. J Neurophysiol. 2006;96:579-90. CrossRef PubMed
  46. Chen Y, Balasubramanyan S, Lai AY, Todd KG, Smith PA. Effects of sciatic nerve axotomy on excitatory synaptic transmission in rat substantia gelatinosa. J Neurophysiol. 2009;102:3203-15. CrossRef PubMed
  47. Biggs JE, Lu VB, Stebbing MJ, Balasubramanyan S, Smith PA. Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Mol Pain. 2010;6:44. CrossRef PubMed PubMedCentral
  48. Lu VB, Ballanyi K, Colmers WF, Smith PA. Neuron typespecific effects of brain-derived neurotrophic factor in rat superficial dorsal horn and their relevance to 'central sensitization'. J Physiol. 2007;584:543-63. CrossRef PubMed PubMedCentral
  49. Lu VB, Biggs JE, Stebbing MJ, Balasubramanyan S, Todd KG, Lai AY, et al. BDNF drives the changes in excitatory synaptic transmission in the rat superficial dorsal horn that follow sciatic nerve injury. J Physiol. 2009;587:1013-32. CrossRef PubMed PubMedCentral
  50. Hildebrand ME, Xu J, Dedek A, Li Y, Sengar AS, Beggs S, Lombroso PJ, Salter MW. Potentiation of synaptic GluN2B NMDAR currents by Fyn kinase is gated through BDNF-mediated disinhibition in spinal pain processing. Cell Rep. 2016;17:2753-65. CrossRef PubMed
  51. Coull JA, Beggs S, Boudreau D, Boivin D, Tsuda M, Inoue K, Gravel C, Salter MW, de Koninck Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature. 2005;438:1017-21. CrossRef PubMed
  52. C.Peirs, R.P.Seal. Neural circuits for pain: Recent advances and current views. Science. 2016;354:578-84. CrossRef PubMed
  53. Peirs C, Williams SP, Zhao X, Walsh CE, Gedeon JY, Cagle NE, et al.Dorsal horn circuits for persistent mechanical pain. Neuron. 2015;87:797-812. CrossRef PubMed PubMedCentral
  54. Baba H, Ji RR, Kohno T, Moore KA, Ataka T, Wakai A, Okamoto M, Woolf CJ. Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn. Mol Cell Neurosci. 2003;24:818-30. CrossRef PubMed
  55. Prescott SA, Ma Q, De KY. Normal and abnormal coding of somatosensory stimuli causing pain. Nat Neurosci. 2014;17:183-91. CrossRef PubMed PubMedCentral
  56. Mapplebeck JCS, Lorenzo LE, Lee KY, Gauthier C, Muley MM, De KY, Prescott SA, Salter MW. Chloride dysregulation through downregulation of KCC2 mediates neuropathic pain in both sexes. Cell Rep. 2019;28:590-6. CrossRef PubMed
  57. Paige C, Plasencia-Fernandez I, Kume M, Papalampropoulou-Tsiridou M, Lorenzo LE, David ET, L He, Mejia GL, Driskill C, et al., A female-specific role for calcitonin gene-related peptide (CGRP) in rodent pain models. J Neurosci. 2022;42:1930-44. CrossRef PubMed PubMedCentral
  58. Alles SRA, Odem MA, Lu VB, Cassidy RM, Smith PA. Chronic BDNF simultaneously inhibits and unmasks superficial dorsal horn neuronal activity. Sci Rep. 2021;11:2249. CrossRef PubMed PubMedCentral
  59. Sandkuhler J. Models and mechanisms of hyperalgesia and allodynia. Physiol Rev. 2009;89:707-58. CrossRef PubMed
  60. Ruscheweyh R, Wilder-Smith O, Drdla R, Liu XG, Sandkuhler J. Long-term potentiation in spinal nociceptive pathways as a novel target for pain therapy. Mol Pain. 2011;7:20. CrossRef PubMed PubMedCentral
  61. Latremoliere A, Woolf CJ. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. Pain. 2009;10:895-926. CrossRef PubMed PubMedCentral
  62. Taylor AMW, Mehrabani S, Liu S, Taylor AJ, Cahill CM. Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. J Neurosci Res. 2016/08/30 (2017) 1330-5. CrossRef PubMed PubMedCentral
  63. von Hehn CA, Baron R, Woolf CJ. Deconstructing the neuropathic pain phenotype to reveal neural mechanisms. Neuron. 2012;73:638-52. CrossRef PubMed PubMedCentral
  64. Zhuo M. Contribution of synaptic plasticity in the insular cortex to chronic pain. Neuroscience. 2016;338:220-9. CrossRef PubMed
  65. Bannister K, Dickenson AH. The plasticity of descending controls in pain: translational probing. J Physiol. 2017;595:4159-66. CrossRef PubMed PubMedCentral
  66. Taylor AM, Castonguay A, Taylor AJ, Murphy NP, Ghogha A, Cook C, Xue L, Olmstead MC, De KY, Evans CJ, Cahill CM. Microglia disrupt mesolimbic reward circuitry in chronic pain. J Neurosci. 2015;35:8442-50. CrossRef PubMed PubMedCentral
  67. Taylor AM, Mehrabani S, Liu S, Taylor AJ, Cahill CM. Topography of microglial activation in sensory- and affect-related brain regions in chronic pain. J Neurosci Res. 2016. CrossRef PubMed PubMedCentral
  68. Fiore NT, Austin PJ. Peripheral nerve injury triggers neuroinflammation in the medial prefrontal cortex and ventral hippocampus in a subgroup of rats with coincident affective behavioral changes. Neuroscience. 2019;416:147-67. CrossRef PubMed
  69. Wu XB, Zhu Q, Gao YJ. CCL2/CCR2 contributes to the altered excitatory-inhibitory synaptic balance in the nucleus accumbens shell following peripheral nerve injury-induced neuropathic pain. Neurosci Bull. 2021;37:921-33. CrossRef PubMed PubMedCentral
  70. Sandy-Hindmarch O, Bennett DL, Wiberg A, Furniss D, Baskozos G, Schmid AB. Systemic inflammatory markers in neuropathic pain, nerve injury, and recovery. Pain. 2022;163:526-37. CrossRef PubMed PubMedCentral
  71. Greenhalgh AD, David S, Bennett FC. Immune cell regulation of glia during CNS injury and disease. Nat Rev Neurosci. 2020;21;139-52. CrossRef PubMed
  72. Ji RR. Specialized pro-resolving mediators as resolution pharmacology for the control of pain and itch. Annu Rev Pharmacol Toxicol. 2022. CrossRef PubMed
  73. Buckley CD, Gilroy DW, Serhan CN, Stockinger B, Tak PP. The resolution of inflammation. Nat Rev Immunol. 2013;13:59-66. CrossRef PubMed
  74. Gabay E, Wolf G, Shavit Y, Yirmiya R, Tal M. Chronic blockade of interleukin-1 (IL-1) prevents and attenuates neuropathic pain behavior and spontaneous ectopic neuronal activity following nerve injury. Eur J Pain. 2011;15:242-8. CrossRef PubMed
  75. Clark AK, D'Aquisto F, Gentry C, Marchand F, McMahon SB, Malcangio M. Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. J Neurochem. 2006;99:868-80. CrossRef PubMed
  76. Yuan Y, Zhao Y, Shen M, Wang C, Dong B, Xie K, Yu Y, Yu Y. Spinal NLRP3 inflammasome activation mediates IL-1beta release and contributes to remifentanil-induced postoperative hyperalgesia by regulating NMDA receptor NR1 subunit phosphorylation and GLT-1 expression in rats. Mol Pain. 2022. 17448069221093016. CrossRef PubMed PubMedCentral
  77. 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;28:5189-94. CrossRef PubMed PubMedCentral
  78. Gustafson-Vickers SL, Lu VB, Lai AY, Todd KG, Ballanyi K, Smith PA. Long-term actions of interleukin-1beta on delay and tonic firing neurons in rat superficial dorsal horn and their relevance to central sensitization. Mol Pain. 2008;4:63. CrossRef PubMed PubMedCentral
  79. Gajtko A, Bakk E, Hegedus K, Ducza L, Hollo K. IL-1beta induced cytokine expression by spinal astrocytes can play a role in the maintenance of chronic inflammatory pain. Front Physiol. 2020;11:543331. CrossRef PubMed PubMedCentral
  80. Stemkowski PL, Garcia-Caballero A, Gadotti VM, Chen L, Souza IA, Zamponi GW. Identification of interleukin-1 beta as a key mediator in the upregulation of Cav3.2GÇôUSP5 interactions in the pain pathway. Mol Pain. 2017;13:1744806917724698. CrossRef PubMed PubMedCentral
  81. Yan X, Li F, Maixner DW, Yadav R, Gao M, Ali MW, Hooks SB, Weng HR. Interleukin-1beta released by microglia initiates the enhanced glutamatergic activity in the spinal dorsal horn during paclitaxel-associated acute pain syndrome. Glia. 2019;67:482-97. CrossRef PubMed
  82. Vasudeva K, Vodovotz Y, Azhar N, Barclay D, Janjic JM, Pollock JA. In vivo and systems biology studies implicate IL-18 as a central mediator in chronic pain. J Neuroimmunol. 2015:283:43-9. CrossRef PubMed PubMedCentral
  83. Miyoshi K, Obata K, Kondo T, Okamura H, Noguchi K. Interleukin-18-mediated microglia/astrocyte interaction in the spinal cord enhances neuropathic pain processing after nerve injury. J Neurosci. 2008;28:12775-87. CrossRef PubMed PubMedCentral
  84. Sommer C, Schmidt C, George A, Toyka KV. A metal loprotease-inhibitor reduces pain associated behavior in mice with experimental neuropathy. Neurosci Lett. 1997;237:45-8. CrossRef PubMed
  85. Wei S, Jin J, Liu T-T, Qiu C-Y, Hu W-P. TNF-alpha acutely enhances acid-sensing ion channel currents in rat dorsal root ganglion neurons via a p38 MAPK pathway. J Neuroinflammat. 2021;18:92. CrossRef PubMed PubMedCentral
  86. Kanda H, Kobayashi K, Yamanaka H, Okubo M, Noguchi K. Microglial TNFalpha induces COX2 and PGI2 synthase expression in spinal endothelial cells during neuropathic pain. eNeuro. 2017;4. CrossRef PubMed PubMedCentral
  87. Shubayev VI, Myers RR. Anterograde TNF alpha transport from rat dorsal root ganglion to spinal cord and injured sciatic nerve. Neurosci Lett. 2002;320:99-101. CrossRef PubMed
  88. Gruber-Schoffnegger D, Drdla-Schutting R, Honigsperger C, Wunderbaldinger G, Gassner M, Sandkuhler J. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-alpha and IL-1beta is mediated by glial cells. J. Neurosci. 2013;33:6540-51. CrossRef PubMed PubMedCentral
  89. del Rivero T, Fischer R, Yang F, Swanson KA, Bethea JR. Tumor necrosis factor receptor 1 inhibition is therapeutic for neuropathic pain in males but not in females. Pain. 2019;160. CrossRef PubMed
  90. Goncalves Dos SG, Delay L, Yaksh TL, Corr M. Neuraxial cytokines in pain states. Front Immunol. 2020;10:3061. CrossRef PubMed PubMedCentral
  91. Abbadie C, Bhangoo S, De KY, Malcangio M, MelikParsadaniantz S, White FA. Chemokines and pain mechanisms. Brain Res Rev. 2009;60:125-34. CrossRef PubMed PubMedCentral
  92. Abbadie C, Lindia JA, Cumiskey AM, Peterson LB, Mudgett JS, Bayne EK, et al. Impaired neuropathic pain responses in mice lacking the chemokine receptor CCR2. Proc Natl Acad Sci USA. 2003;100:7947-52. CrossRef PubMed PubMedCentral
  93. Sun JH, Yang B, Donnelly DF, Ma C, LaMotte RH. MCP-1 enhances excitability of nociceptive neurons in chronically compressed dorsal root ganglia. J Neurophysiol. 2006;96:2189-99. CrossRef PubMed
  94. Jung H, Bhangoo S, Banisadr G, Freitag C, Ren D, White FA, Miller RJ, Visualization of chemokine receptor activation in transgenic mice reveals peripheral activation of CCR2 receptors in states of neuropathic pain. J Neurosci. 2009;29:8051-62. CrossRef PubMed PubMedCentral
  95. Sorge RE, SiY, Norian LA, Guha A, Moore GE, Nabors LB, Filippova N, Yang X, Smith R, Chellappan R, King PH. Inhibition of the RNA regulator HuR by SRI42127 attenuates neuropathic pain after nerve injury through suppression of neuroinflammatory responses. Neurotherapeutics. 2022. CrossRef PubMed
  96. Piotrowska A, Rojewska E, Pawlik K, Kreiner G, Ciechanowska A, Makuch W, Zychowska M, Mika J. Pharmacological blockade of CXCR3 by (+/-)-NBI74330 reduces neuropathic pain and enhances opioid effectiveness - evidence from in vivo and in vitro studies. Biochim Biophys Acta Mol Basis Dis. 2018;1864: 3418-37. CrossRef PubMed
  97. de Jong EK, Vinet J, Stanulovic VS, Meijer M, Wesseling E, Sjollema K, Boddeke HW, Biber K. Expression, transport, and axonal sorting of neuronal CCL21 in large dense-core vesicles. FASEB J. 2008;22:4136-45. CrossRef PubMed
  98. Honjoh K, Nakajima H, Hirai T, Watanabe S, Matsumine A. Relationship of inflammatory cytokines from M1-type microglia/macrophages at the injured site and lumbar enlargement with neuropathic pain after spinal cord injury in the CCL21 knockout (plt) mouse. Front Cell Neurosci. 2019;13:525. CrossRef PubMed PubMedCentral
  99. Dong J, Xia R, Zhang Z, Xu C. lncRNA MEG3 aggravated neuropathic pain and astrocyte overaction through mediating miR-130a-5p/CXCL12/CXCR4 axis. Aging (Albany NY). 2021;13:23004-19. CrossRef PubMed PubMedCentral
  100. 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;154:2185-97. CrossRef PubMed PubMedCentral
  101. Luo X, Tai WL, Sun L, Pan Z, Xia Z, Chung SK, Cheung CW. Crosstalk between astrocytic CXCL12 and microglial CXCR4 contributes to the development of neuropathic pain. Mol Pain. 2016;12. CrossRef PubMed PubMedCentral
  102. da Silva Junior CA, de Castro Junior CJ, Pereira EMR, Binda NS, da Silva JF, et al. The inhibitory effect of Phalpha1beta toxin on diabetic neuropathic pain involves the CXCR4 chemokine receptor. Pharmacol Rep. 2020;72:47-54. CrossRef PubMed
  103. Yang F, Sun W, Luo WJ, Yang Y, Yang F, Wang XL, Chen J. SDF1-CXCR4 signaling contributes to the transition from acute to chronic pain state. Mol Neurobiol. 2017;54:2763-75. CrossRef PubMed
  104. Lindia JA, McGowan E, Jochnowitz N, Abbadie C. Induction of CX3CL1 expression in astrocytes and CX3CR1 in microglia in the spinal cord of a rat model of neuropathic pain. Pain. 2005;6:434-8. CrossRef PubMed
  105. Milligan ED, Zapata V, Chacur M, Schoeniger D, Biedenkapp J, O'connor KA, Verge GM, Chapman G, et al. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci. 2004;20:2294-302. CrossRef PubMed
  106. Staniland AA, Clark AK, Wodarski R, Sasso O, F Maione, D'Acquisto F, Malcangio M. Reduced inflammatory and neuropathic pain and decreased spinal microglial response in fractalkine receptor (CX3CR1) knockout mice. J Neurochem. 2010;114:1143-57. CrossRef PubMed
  107. Clark AK, Yip PK, Malcangio M. The liberation of fractalkine in the dorsal horn requires microglial cathepsin S. J Neurosci. 2009;29:6945-54. CrossRef PubMed PubMedCentral
  108. Clark AK, Gruber-Schoffnegger D, Drdla-Schutting R, Gerhold KJ, Malcangio M, Sandkuhler J. Selective activation of microglia facilitates synaptic strength. J Neurosci. 2015;35:4552-70. CrossRef PubMed PubMedCentral
  109. Clark AK, Wodarski R, Guida F, Sasso O, Malcangio M. Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia. 2010;58:1710-26. CrossRef PubMed
  110. Tsuda M, Masuda T, Kitano J, Shimoyama H, TozakiSaitoh H, Inoue K. IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proc Natl Acad Sci USA. 2009;106:8032-7. CrossRef PubMed PubMedCentral
  111. Vikman KS, Duggan AW, Siddall PJ. Interferon-gamma induced disruption of GABAergic inhibition in the spinal dorsal horn in vivo. Pain. 2007;133:18-28. CrossRef PubMed
  112. Reischer G, Heinke B, Sandkuhler J. Interferon gamma facilitates the synaptic transmission between primary afferent C-fibres and lamina I neurons in the rat spinal dorsal horn via microglia activation. Mol Pain. 2020;16:1744806920917249. CrossRef PubMed PubMedCentral
  113. Costigan M, Moss A, Latremoliere A, Johnston C, VermaGandhu M, Herbert TA, Barrett L, et al. T-cell infiltration and signaling in the adult dorsal spinal cord is a major contributor to neuropathic pain-like hypersensitivity. J Neurosci. 2009;29:14415-22. CrossRef PubMed PubMedCentral
  114. Hirth M, Rukwied R, Gromann A, Turnquist B, Weinkauf B, Francke K, Albrecht P, Rice F, et al. Nerve growth factor induces sensitization of nociceptors without evidence for increased intraepidermal nerve fiber density. Pain. 2013;154:2500-11. CrossRef PubMed
  115. Thoenen H, Bandtlow C, Heumann R, Lindholm D, Meyer M, Rohrer H. Nerve growth factor: cellular localization and regulation of synthesis. Cell Mol Neurobiol. 1988;8:35-40. CrossRef PubMed
  116. Hefti F. Pharmacology of nerve growth factor and discovery of tanezumab, an anti-nerve growth factor antibody and pain therapeutic. Pharmacol Res. 2020; 154:104240. CrossRef PubMed
  117. Boakye PA, Rancic V, Whitlock KH, Simmons D, Longo FM, Ballanyi K, Smith PA. Receptor dependence of BDNF actions in superficial dorsal horn: relation to central sensitization and actions of macrophage colony stimulating factor 1. J Neurophysiol. 2019;121:2308-22. CrossRef PubMed
  118. Yu X, Basbaum A, Guan Z. Contribution of colonystimulating factor 1 to neuropathic pain. PAIN Rep. 2021;6. CrossRef PubMed PubMedCentral
  119. Lim H, Lee H, Noh K, Lee SJ. IKK/NF-kappaBdependent satellite glia activation induces spinal cord microglia activation and neuropathic pain after nerve injury. Pain. 2017;158:1666-77. CrossRef PubMed
  120. Yu X, Liu H, Hamel KA, Morvan MG, Yu S, Leff J, Guan Z, Braz JM, Basbaum AI. Dorsal root ganglion macrophages contribute to both the initiation and persistence of neuropathic pain. Nat Commun. 2020;11:264. CrossRef PubMed PubMedCentral
  121. Yang G, Tan Q, Li Z, Liu K, Wu J, Ye W, Mei H, Yu H. The AMPK pathway triggers autophagy during CSF1-induced microglial activation and may be implicated in inducing neuropathic pain. J Neuroimmunol. 2020;345:577261. CrossRef PubMed
  122. Sun C, Tao X, Wan C, Zhang X, Zhao M, Xu M, Wang P, Liu Y, Wang C, Xi Q, Song T. Spinal cord stimulation alleviates neuropathic pain by attenuating microglial activation via reducing colony-stimulating factor 1 levels in the spinal cord in a rat model of chronic constriction injury. Anesth Analg. 2022;135:178-90. CrossRef PubMed PubMedCentral
  123. Gushchina S, Pryce G, Yip PK, Wu D, Pallier P, Giovannoni G, Baker D, Bo X. Increased expression of colony-stimulating factor-1 in mouse spinal cord with experimental autoimmune encephalomyelitis correlates with microglial activation and neuronal loss. Glia. 2018;66:2108-25. CrossRef PubMed
  124. Yu X, Basbaum A, Guan Z. Contribution of colonystimulating factor 1 to neuropathic pain. Pain Rep. 2021;6: e883. CrossRef PubMed PubMedCentral
  125. Lee J, Hwang H, Lee SJ. Distinct roles of GT1b and CSF-1 in microglia activation in nerve injury-induced neuropathic pain. Mol Pain. 2021;17: 17448069211020918. CrossRef PubMed PubMedCentral
  126. Kuhn JA, Vainchtein ID, Braz J, Hamel K, Bernstein M, Craik V, et al. Regulatory T-cells inhibit microgliainduced pain hypersensitivity in female mice. Elife. 2021;10. CrossRef PubMed PubMedCentral
  127. Smith PA. BDNF: No gain without pain? Neuroscience. 2014;283:107-23. CrossRef PubMed
  128. Li S, Cai J, Feng ZB, Jin ZR, Liu BH, Zhao HY, Jing HB, Wei TJ, Yang GN, Liu LY, Cui YJ, Xing GG. BDNF contributes to spinal long-term potentiation and mechanical hypersensitivity via fyn-mediated phosphorylation of NMDA receptor GluN2B subunit at tyrosine 1472 in rats following spinal nerve ligation. Neurochem Res. 2017;42: 2712-29. CrossRef PubMed
  129. Masuda T, Ozono Y, Mikuriya S, Kohro Y, TozakiSaitoh H, Iwatsuki K, Uneyama H, et al. Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat Commun. 2016;7:12529. CrossRef PubMed PubMedCentral
  130. Beggs S, Trang T, Salter MW. P2X4R+ microglia drive neuropathic pain. Nat Neurosci. 2012;15:1068-73. CrossRef PubMed PubMedCentral
  131. Zhang W, Shi Y, Peng Y, Zhong L, Zhu S, Zhang W, Tang SJ. Neuron activity-induced Wnt signaling up-regulates expression of brain-derived neurotrophic factor in the pain neural circuit. J Biol Chem. 2018;293:15641-51. CrossRef PubMed PubMedCentral
  132. Kerr BJ, Bradbury EJ, Bennett DL, Trivedi PM, Dassan P, French J, Shelton DB, McMahon SB, Thompson SW. Brain-derived neurotrophic factor modulates nociceptive sensory inputs and NMDA-evoked responses in the rat spinal cord. J Neurosci. 1999;19:5138-48. CrossRef PubMed PubMedCentral
  133. Chen W, Walwyn W, Ennes HS, Kim H, McRoberts JA, Marvizon JC. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminals. Eur J Neurosci. 2014;39:1439-54. CrossRef PubMed PubMedCentral
  134. Ferrini F, Perez-Sanchez J, Ferland S, Lorenzo LE, Godin AG, Plasencia-Fernandez I, Cottet M, et al.Differential chloride homeostasis in the spinal dorsal horn locally shapes synaptic metaplasticity and modality-specific sensitization. Nat Commun. 2020;11:3935. CrossRef PubMed PubMedCentral
  135. Lavertu G, Côté S, de Koninck Y. Enhancing K-Cl cotransport restores normal spinothalamic sensory coding in a neuropathic pain model. Brain. 2014;137:724-38. CrossRef PubMed
  136. Prescott SA, de Koninck Y, Sejnowski TJ. Biophysical basis for three distinct dynamical mechanisms of action potential initiation. PLoS Comput Biol. 2008;4:e1000198. CrossRef PubMed PubMedCentral
  137. Ferrini F, de Koninck Y. Microglia control neuronal network excitability via BDNF signalling. Neural Plast. 2013;2013: 429815. CrossRef PubMed PubMedCentral
  138. Price TJ, Prescott SA. Inhibitory regulation of the pain gate and how its failure causes pathological pain. Pain. 2015;156:789-92. CrossRef PubMed PubMedCentral
  139. Sandkuhler J, Benrath J, Brechtel C, Ruscheweyh R, Heinke B. Synaptic mechanisms of hyperalgesia. Prog Brain Res. 2000;129:81-100. CrossRef PubMed
  140. Sandkuhler J. Understanding LTP in pain pathways. Mol Pain. 2007;3:9. CrossRef PubMed PubMedCentral
  141. Ding X, Cai J, Li S, Liu XD, Wan Y, Xing GG. BDNF contributes to the development of neuropathic pain by induction of spinal long-term potentiation via SHP2 associated GluN2B-containing NMDA receptors activation in rats with spinal nerve ligation. Neurobiol Dis. 2015;73:428-51. CrossRef PubMed
  142. Zhou LJ, Peng J, Xu YN, Zeng WJ, Zhang J, Wei X, Mai CL, Lin ZJ, et al. Microglia Are indispensable for synaptic plasticity in the spinal dorsal horn and chronic pain. Cell Rep. 2019;29:3844-59. CrossRef PubMed PubMedCentral
  143. Zhang X, Wang J, Zhou Q, Xu Y, Pu S, Wu J, Xue Y, Tian Y, Lu J, Jiang W, Du D. Brain-derived neurotrophic factor-activated astrocytes produce mechanical allodynia in neuropathic pain. Neuroscience. 2011;199:452-60. CrossRef PubMed
  144. Ji RR, Donnelly CR, Nedergaard M. Astrocytes in chronic pain and itch. Nat Rev Neurosci. 2019;20:667-85. CrossRef PubMed PubMedCentral
  145. Dougherty KD, Dreyfus CF, Black IB. Brain-derived neurotrophic factor in astrocytes, oligodendrocytes, and microglia/macrophages after spinal cord injury. Neurobiol. Dis. 2000;7: 574-85. CrossRef PubMed
  146. Pineau I, Lacroix S. Proinflammatory cytokine synthesis in the injured mouse spinal cord: Multiphasic expression pattern and identification of the cell types involved. J Comp Neurol. 2007;500:267-85. CrossRef PubMed
  147. Baron R, Maier C, Attal N, Binder A, Bouhassira D, Cruccu G, Finnerup NB, Haanpaa M, Hansson P, Hullemann P, Jensen TS, et alPeripheral neuropathic pain: a mechanism-related organizing principle based on sensory profiles. Pain. 2017;158:261-72. CrossRef PubMed PubMedCentral
  148. Scholz J, Tegeder I, Griffin RS, Woolf CJ. Models of peripheral neuropathic pain produce distinct patterns of immune cell activation and transcriptional regulation in the spinal cord. 2004 Abstract Viewer/Itinerary Planner. Washington, DC: Society for Neuroscience, Online 2004. Program No. 518.9.
  149. Kleinschnitz C, Brinkhoff J, Zelenka M, Sommer C, Stoll G. The extent of cytokine induction in peripheral nerve lesions depends on the mode of injury and NMDA receptor signaling. J Neuroimmunol. 2004;149:77-83. CrossRef PubMed

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.