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Review

Normalization of Neuroinflammation: A New Strategy for Treatment of Persistent Pain and Memory/Emotional Deficits in Chronic Pain

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Pages 5201-5233 | Published online: 09 Sep 2022

References

  • Toth C, Lander J, Wiebe S. The prevalence and impact of chronic pain with neuropathic pain symptoms in the general population. Pain Med. 2009;10(5):918–929. doi:10.1111/j.1526-4637.2009.00655.x
  • Mohamed Zaki LR, Hairi NN. A systematic review of the prevalence and measurement of chronic pain in Asian adults. Pain Manage Nurs. 2015;16(3):440–452. doi:10.1016/j.pmn.2014.08.012
  • Jank R, Gallee A, Boeckle M, Fiegl S, Pieh C. Chronic pain and sleep disorders in primary care. Pain Res Treat. 2017;2017:9081802. doi:10.1155/2017/9081802
  • Means-Christensen AJ, Roy-Byrne PP, Sherbourne CD, Craske MG, Stein MB. Relationships among pain, anxiety, and depression in primary care. Depress Anxiety. 2008;25(7):593–600. doi:10.1002/da.20342
  • Hart RP, Wade JB, Martelli MF. Cognitive impairment in patients with chronic pain: the significance of stress. CurrPain Headache Rep. 2003;7(2):116–126. doi:10.1007/s11916-003-0021-5
  • Whitlock EL, Diaz-Ramirez LG, Glymour MM, Boscardin WJ, Covinsky KE, Smith AK. Association between persistent pain and memory decline and dementia in a longitudinal cohort of elders. JAMA Intern Med. 2017;177(8):1146–1153. doi:10.1001/jamainternmed.2017.1622
  • Nahin RL, DeKosky ST. Comorbid pain and cognitive impairment in a nationally representative adult population: prevalence and associations with health status, health care utilization, and satisfaction with care. Clin J Pain. 2020;36(10):725–739. doi:10.1097/AJP.0000000000000863
  • Mäntyselkä P, Kumpusalo E, Ahonen R, et al. Pain as a reason to visit the doctor: a study in Finnish primary health care. Pain. 2001;89(2–3):175–180. doi:10.1016/S0304-3959(00)00361-4
  • Raja SN, Carr DB, Cohen M, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161:1976–1982. doi:10.1097/j.pain.0000000000001939
  • Treede RD, Rief W, Barke A, et al. A classification of chronic pain for ICD-11. Pain. 2015;156(6):1003–1007. doi:10.1097/j.pain.0000000000000160
  • Goldberg DS, McGee SJ. Pain as a global public health priority. BMC Public Health. 2011;11:770. doi:10.1186/1471-2458-11-770
  • Cohen SP, Vase L, Hooten WM. Chronic pain: an update on burden, best practices, and new advances. Lancet. 2021;397(10289):2082–2097. doi:10.1016/S0140-6736(21)00393-7
  • Dieppe PA, Lohmander LS. Pathogenesis and management of pain in osteoarthritis. Lancet. 2005;365(9463):965–973. doi:10.1016/S0140-6736(05)71086-2
  • Treede RD, Jensen TS, Campbell JN, et al. Neuropathic pain: redefinition and a grading system for clinical and research purposes. Neurology. 2008;70(18):1630–1635. doi:10.1212/01.wnl.0000282763.29778.59
  • Bennett GJ, Xie YK. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain. 1988;33(1):87–107. doi:10.1016/0304-3959(88)90209-6
  • Kim SH, Chung JM. An experimental model for peripheral neuropathy produced by segmental spinal nerve ligation in the rat. Pain. 1992;50(3):355–363. doi:10.1016/0304-3959(92)90041-9
  • Decosterd I, Woolf CJ. Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain. 2000;87(2):149–158. doi:10.1016/S0304-3959(00)00276-1
  • Li L, Xian CJ, Zhong JH, Zhou XF. Effect of lumbar 5 ventral root transection on pain behaviors: a novel rat model for neuropathic pain without axotomy of primary sensory neurons. ExpNeurol. 2002;175(1):23–34.
  • Polomano RC, Mannes AJ, Clark US, Bennett GJ. A painful peripheral neuropathy in the rat produced by the chemotherapeutic drug, paclitaxel. Pain. 2001;94(3):293–304. doi:10.1016/S0304-3959(01)00363-3
  • Siau C, Bennett GJ. Dysregulation of cellular calcium homeostasis in chemotherapy-evoked painful peripheral neuropathy. Anesth Analg. 2006;102(5):1485–1490. doi:10.1213/01.ane.0000204318.35194.ed
  • Zychowska M, Rojewska E, Przewlocka B, Mika J. Mechanisms and pharmacology of diabetic neuropathy - experimental and clinical studies. Pharmacol Rep. 2013;65(6):1601–1610. doi:10.1016/S1734-1140(13)71521-4
  • Kosek E, Cohen M, Baron R, et al. Do we need a third mechanistic descriptor for chronic pain states? Pain. 2016;157(7):1382–1386. doi:10.1097/j.pain.0000000000000507
  • Fitzcharles MA, Cohen SP, Clauw DJ, Littlejohn G, Usui C, Häuser W. Nociplastic pain: towards an understanding of prevalent pain conditions. Lancet. 2021;397(10289):2098–2110. doi:10.1016/S0140-6736(21)00392-5
  • Zhou LJ, Peng J, Xu YN, et al. Microglia are indispensable for synaptic plasticity in the spinal dorsal horn and chronic pain. Cell Rep. 2019;27(13):3844–3859 e3846. doi:10.1016/j.celrep.2019.05.087
  • Liu Y, Zhou LJ, Wang J, et al. TNF-alpha differentially regulates synaptic plasticity in the hippocampus and spinal cord by microglia-dependent mechanisms after peripheral nerve injury. J Neurosci. 2017;37(4):871–881. doi:10.1523/JNEUROSCI.2235-16.2016
  • Wei XH, Centeno MV, Ren WJ, et al. Activation of the dorsal, but not the ventral, hippocampus relieves neuropathic pain in rodents. Pain. 2021;162(12):2865–2880. doi:10.1097/j.pain.0000000000002279
  • Zhang J, Mai CL, Xiong Y, et al. The causal role of magnesium deficiency in the neuroinflammation, pain hypersensitivity and memory/emotional deficits in ovariectomized and aged female mice. J Inflamm Res. 2021;14:6633–6656. doi:10.2147/JIR.S330894
  • Ren WJ, Liu Y, Zhou LJ, et al. Peripheral nerve injury leads to working memory deficits and dysfunction of the hippocampus by upregulation of TNF-alpha in rodents. Neuropsychopharmacology. 2011;36(5):979–992. doi:10.1038/npp.2010.236
  • Xu T, Li D, Zhou X, et al. Oral application of magnesium-l-threonate attenuates vincristine-induced allodynia and hyperalgesia by normalization of tumor necrosis factor-alpha/nuclear factor-kappaB signaling. Anesthesiology. 2017;126(6):1151–1168. doi:10.1097/ALN.0000000000001601
  • Zhou X, Huang Z, Zhang J, et al. Chronic oral administration of magnesium-L-threonate prevents oxaliplatin-induced memory and emotional deficits by normalization of TNF-α/NF-κB signaling in rats. Neurosci Bull. 2020;37(1):55–69. doi:10.1007/s12264-020-00563-x
  • Drdla-Schutting R, Heinl C, Hadschieff V, Sandkühler J. Withdrawal from an opioid induces a transferable memory trace in the cerebrospinal fluid. Pain. 2019;160(12):2819–2828. doi:10.1097/j.pain.0000000000001688
  • Wall PD, Gutnick M. Ongoing activity in peripheral nerves: the Physiology and pharmacology of impulses originating from a neuroma. Exp Neurol. 1974;43(3):580–593. doi:10.1016/0014-4886(74)90197-6
  • Devor M. Ectopic discharge in Abeta afferents as a source of neuropathic pain. ExpBrain Res. 2009;196(1):115–128.
  • Roza C, Bernal L. Electrophysiological characterization of ectopic spontaneous discharge in axotomized and intact fibers upon nerve transection: a role in spontaneous pain? Pflugers Archiv. 2022;474(4):387–396. doi:10.1007/s00424-021-02655-7
  • Woolf CJ. Evidence for a central component of post-injury pain hypersensitivity. Nature. 1983;306(5944):686–688. doi:10.1038/306686a0
  • Basbaum AI. Distinct neurochemical features of acute and persistent pain. ProcNatlAcadSciUSA. 1999;96(14):7739–7743. doi:10.1073/pnas.96.14.7739
  • Treede RD, Rief W, Barke A, et al. Chronic pain as a symptom or a disease: the IASP classification of chronic pain for the International Classification of Diseases (ICD-11). Pain. 2019;160(1):19–27. doi:10.1097/j.pain.0000000000001384
  • Scholz J, Woolf CJ. Can we conquer pain? NatNeurosci. 2002;5:1062–1067.
  • Dib-Hajj SD, Waxman SG. Sodium channels in human pain disorders: genetics and pharmacogenomics. Annu Rev Neurosci. 2019;42:87–106. doi:10.1146/annurev-neuro-070918-050144
  • Goodwin G, McMahon SB. The physiological function of different voltage-gated sodium channels in pain. Nat Rev Neurosci. 2021;22(5):263–274. doi:10.1038/s41583-021-00444-w
  • Yang J, Xie MX, Hu L, et al. Upregulation of N-type calcium channels in the soma of uninjured dorsal root ganglion neurons contributes to neuropathic pain by increasing neuronal excitability following peripheral nerve injury. Brain Behav Immun. 2018;71:52–65. doi:10.1016/j.bbi.2018.04.016
  • Hoppanova L, Lacinova L. Voltage-dependent Ca(V)3.2 and Ca(V)2.2 channels in nociceptive pathways. Pflugers Archiv. 2022;474:421–434. doi:10.1007/s00424-022-02666-y
  • Smith PA. K(+) channels in primary afferents and their role in nerve injury-induced pain. Front Cell Neurosci. 2020;14:566418. doi:10.3389/fncel.2020.566418
  • Iannone LF, De Logu F, Geppetti P, De Cesaris F. The role of TRP ion channels in migraine and headache. Neurosci Lett. 2022;768:136380. doi:10.1016/j.neulet.2021.136380
  • Go EJ, Ji J, Kim YH, Berta T, Park CK. Transient receptor potential channels and botulinum neurotoxins in chronic pain. Front Mol Neurosci. 2021;14:772719. doi:10.3389/fnmol.2021.772719
  • Wemmie JA, Taugher RJ, Kreple CJ. Acid-sensing ion channels in pain and disease. Nat Rev Neurosci. 2013;14(7):461–471. doi:10.1038/nrn3529
  • Liu XG, Zhou LJ. Long-term potentiation at spinal C-fiber synapses: a target for pathological pain. Curr Pharm Des. 2015;21(7):895–905. doi:10.2174/1381612820666141027115949
  • Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26(12):696–705. doi:10.1016/j.tins.2003.09.017
  • Eccleston C. Chronic pain and distraction: an experimental investigation into the role of sustained and shifting attention in the processing of chronic persistent pain. Behav Res Ther. 1995;33(4):391–405. doi:10.1016/0005-7967(94)00057-Q
  • Legrain V, Damme SV, Eccleston C, Davis KD, Seminowicz DA, Crombez G. A neurocognitive model of attention to pain: behavioral and neuroimaging evidence. Pain. 2009;144(3):230–232. doi:10.1016/j.pain.2009.03.020
  • Etherton JL, Bianchini KJ, Ciota MA, Heinly MT, Greve KW. Pain, malingering and the WAIS-III working memory index. Spine J. 2006;6(1):61–71. doi:10.1016/j.spinee.2005.05.382
  • Dick BD, Rashiq S. Disruption of attention and working memory traces in individuals with chronic pain. Anesthesia Analgesia. 2007;104(5):1223–1229. doi:10.1213/01.ane.0000263280.49786.f5
  • Blackburn-Munro G, Blackburn-Munro RE. Chronic pain, chronic stress and depression: coincidence or consequence? J Neuroendocrinol. 2001;13(12):1009–1023. doi:10.1046/j.0007-1331.2001.00727.x
  • Yalcin I, Barrot M. The anxiodepressive comorbidity in chronic pain. Curr Opin Anaesthesiol. 2014;27(5):520–527. doi:10.1097/ACO.0000000000000116
  • Fishbain DA, Cutler R, Rosomoff HL, Rosomoff RS. Chronic pain-associated depression: antecedent or consequence of chronic pain? A review. Clin J Pain. 1997;13(2):116–137. doi:10.1097/00002508-199706000-00006
  • Magni G, Moreschi C, Rigatti-Luchini S, Merskey H. Prospective study on the relationship between depressive symptoms and chronic musculoskeletal pain. Pain. 1994;56(3):289–297. doi:10.1016/0304-3959(94)90167-8
  • Kuner R. Central mechanisms of pathological pain. Nat Med. 2010;16(11):1258–1266. doi:10.1038/nm.2231
  • Schwartz M, Deczkowska A. Neurological disease as a failure of brain-immune crosstalk: the multiple faces of neuroinflammation. Trends Immunol. 2016;37(10):668–679. doi:10.1016/j.it.2016.08.001
  • Gui WS, Wei X, Mai CL, et al. Interleukin-1beta overproduction is a common cause for neuropathic pain, memory deficit, and depression following peripheral nerve injury in rodents. Mol Pain. 2016;12:174480691664678. doi:10.1177/1744806916646784
  • Guimarães MR, Soares AR, Cunha AM, et al. Evidence for lack of direct causality between pain and affective disturbances in a rat peripheral neuropathy model. Genes Brain Behav. 2019;18(6):e12542. doi:10.1111/gbb.12542
  • Holtmaat A, Svoboda K. Experience-dependent structural synaptic plasticity in the mammalian brain. Nat Rev Neurosci. 2009;10(9):647–658. doi:10.1038/nrn2699
  • Bliss TV, Collingridge GL. A synaptic model of memory: long-term potentiation in the hippocampus. Nature. 1993;361(6407):31–39. doi:10.1038/361031a0
  • Neves G, Cooke SF, Bliss TVP. Synaptic plasticity, memory and the hippocampus: a neural network approach to causality. Nat Rev Neurosci. 2008;9(1):65–75. doi:10.1038/nrn2303
  • Cannon BW. The Wisdom of the Body. New York: Norton \& Co.; 1932.
  • Zhou LJ, Xin WJ, Pang RP, Liu XG. Cytokine microenvironment hypothesis of chronic pain. Chin J Pain Med. 2013;19(11):679–684.
  • Zhang JM, An J. Cytokines, inflammation, and pain. Int Anesthesiol Clin. 2007;45(2):27–37. doi:10.1097/AIA.0b013e318034194e
  • Dinarello CA. Historical insights into cytokines. Eur J Immunol. 2007;37(Suppl1):S34–45. doi:10.1002/eji.200737772
  • Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. doi:10.1146/annurev.iy.12.040194.001041
  • Kabata H, Artis D. Neuro-immune crosstalk and allergic inflammation. J Clin Invest. 2019;129(4):1475–1482. doi:10.1172/JCI124609
  • Wei XH, Zang Y, Wu CY, Xu JT, Xin WJ, Liu XG. Peri-sciatic administration of recombinant rat TNF-alpha induces mechanical allodynia via upregulation of TNF-alpha in dorsal root ganglia and in spinal dorsal horn: the role of NF-kappa B pathway. ExpNeurol. 2007;205(2):471–484.
  • Morris P, Ali K, Merritt M, Pelletier J, Macedo LG. A systematic review of the role of inflammatory biomarkers in acute, subacute and chronic non-specific low back pain. BMC Musculoskelet Disord. 2020;21(1):142. doi:10.1186/s12891-020-3154-3
  • Ernberg M, Christidis N, Ghafouri B, et al. Plasma cytokine levels in fibromyalgia and their response to 15 weeks of progressive resistance exercise or relaxation therapy. Mediators Inflamm. 2018;2018:3985154. doi:10.1155/2018/3985154
  • Ingegnoli F, Fantini F, Favalli EG, et al. Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: effects of tumor necrosis factor-alpha blockade. J Autoimmun. 2008;31(2):175–179. doi:10.1016/j.jaut.2008.07.002
  • Oliveira AB, Bachi ALL, Ribeiro RT, Mello MT, Tufik S, Peres MFP. Unbalanced plasma TNF-α and IL-12/IL-10 profile in women with migraine is associated with psychological and physiological outcomes. J Neuroimmunol. 2017;313:138–144. doi:10.1016/j.jneuroim.2017.09.008
  • Xu JT, Xin WJ, Zang Y, Wu CY, Liu XG. The role of tumor necrosis factor-alpha in the neuropathic pain induced by Lumbar 5 ventral root transection in rat. Pain. 2006;123(3):306–321. doi:10.1016/j.pain.2006.03.011
  • Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states. Pain. 1995;63(3):289–302. doi:10.1016/0304-3959(95)00186-7
  • Chen SX, Liao GJ, Yao PW, et al. Calpain-2 regulates TNF-alpha expression associated with neuropathic pain following motor nerve injury. Neuroscience. 2018;376:142–151. doi:10.1016/j.neuroscience.2018.02.023
  • Nadeau S, Filali M, Zhang J, et al. Functional recovery after peripheral nerve injury is dependent on the pro-inflammatory cytokines IL-1β and TNF: implications for neuropathic pain. J Neurosci. 2011;31(35):12533–12542. doi:10.1523/JNEUROSCI.2840-11.2011
  • Zhang J, Su YM, Li D, et al. TNF-alpha-mediated JNK activation in the dorsal root ganglion neurons contributes to Bortezomib-induced peripheral neuropathy. Brain Behav Immun. 2014;38:185–191. doi:10.1016/j.bbi.2014.01.020
  • Yamakawa I, Kojima H, Terashima T, et al. Inactivation of TNF-α ameliorates diabetic neuropathy in mice. Am J Physiol Endocrinol Metab. 2011;301(5):E844–852. doi:10.1152/ajpendo.00029.2011
  • Chen X, Pang RP, Shen KF, et al. TNF-alpha enhances the currents of voltage gated sodium channels in uninjured dorsal root ganglion neurons following motor nerve injury. Exp Neurol. 2011;227:279–286. doi:10.1016/j.expneurol.2010.11.017
  • Zelenka M, Schafers M, Sommer C. Intraneural injection of interleukin-1beta and tumor necrosis factor-alpha into rat sciatic nerve at physiological doses induces signs of neuropathic pain. Pain. 2005;116(3):257–263. doi:10.1016/j.pain.2005.04.018
  • Wei XH, Yang T, Wu Q, et al. Peri-sciatic administration of recombinant rat IL-1beta 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
  • Muscat SM, Barrientos RM. The perfect cytokine storm: how peripheral immune challenges impact brain plasticity & memory function in aging. Brain plast. 2021;7(1):47–60. doi:10.3233/BPL-210127
  • Decourt B, Lahiri DK, Sabbagh MN. Targeting tumor necrosis factor alpha for Alzheimer’s disease. Curr Alzheimer Res. 2017;14(4):412–425. doi:10.2174/1567205013666160930110551
  • Miller AH, Maletic V, Raison CL. Inflammation and its discontents: the role of cytokines in the pathophysiology of major depression. Biol Psychiatry. 2009;65(9):732–741. doi:10.1016/j.biopsych.2008.11.029
  • Jia X, Gao Z, Hu H. Microglia in depression: current perspectives. Sci China Life Sci. 2021;64(6):911–925. doi:10.1007/s11427-020-1815-6
  • Norman GJ, Karelina K, Zhang N, Walton JC, Morris JS, Devries AC. Stress and IL-1beta contribute to the development of depressive-like behavior following peripheral nerve injury. Mol Psychiatry. 2010;15(4):404–414. doi:10.1038/mp.2009.91
  • Bennett DL, Clark AJ, Huang J, Waxman SG, Dib-Hajj SD. The role of voltage-gated sodium channels in pain signaling. Physiol Rev. 2019;99(2):1079–1151. doi:10.1152/physrev.00052.2017
  • Cox JJ, Reimann F, Nicholas AK, et al. An SCN9A channelopathy causes congenital inability to experience pain. Nature. 2006;444(7121):894–898. doi:10.1038/nature05413
  • Fertleman CR, Baker MD, Parker KA, et al. SCN9A mutations in paroxysmal extreme pain disorder: allelic variants underlie distinct channel defects and phenotypes. Neuron. 2006;52(5):767–774. doi:10.1016/j.neuron.2006.10.006
  • Faber CG, Lauria G, Merkies IS, et al. Gain-of-function Nav1.8 mutations in painful neuropathy. Proc Natl Acad Sci U S A. 2012;109(47):19444–19449. doi:10.1073/pnas.1216080109
  • Han C, Vasylyev D, Macala LJ, et al. The G1662S NaV1.8 mutation in small fibre neuropathy: impaired inactivation underlying DRG neuron hyperexcitability. J Neurol Neurosurg Psychiatry. 2014;85(5):499–505. doi:10.1136/jnnp-2013-306095
  • Huang J, Han C, Estacion M, et al. Gain-of-function mutations in sodium channel Na(v)1.9 in painful neuropathy. Brain. 2014;137(Pt 6):1627–1642. doi:10.1093/brain/awu079
  • Zhang XY, Wen J, Yang W, et al. Gain-of-function mutations in SCN11A cause familial episodic pain. Am J Hum Genet. 2013;93(5):957–966. doi:10.1016/j.ajhg.2013.09.016
  • Black JA, Frezel N, Dib-Hajj SD, Waxman SG. Expression of Nav1.7 in DRG neurons extends from peripheral terminals in the skin to central preterminal branches and terminals in the dorsal horn. Mol Pain. 2012;8:82. doi:10.1186/1744-8069-8-82
  • Toledo-Aral JJ, Moss BL, He ZJ, et al. Identification of PN1, a predominant voltage-dependent sodium channel expressed principally in peripheral neurons. Proc Natl Acad Sci U S A. 1997;94(4):1527–1532. doi:10.1073/pnas.94.4.1527
  • Rush AM, Dib-Hajj SD, Liu S, Cummins TR, Black JA, Waxman SG. A single sodium channel mutation produces hyper- or hypoexcitability in different types of neurons. Proc Natl Acad Sci U S A. 2006;103(21):8245–8250. doi:10.1073/pnas.0602813103
  • Alles SRA, Nascimento F, Luján R, et al. Sensory neuron-derived Na(V)1.7 contributes to dorsal horn neuron excitability. Sci Adv. 2020;6(8):eaax4568. doi:10.1126/sciadv.aax4568
  • Minett MS, Nassar MA, Clark AK, et al. Distinct Nav1.7-dependent pain sensations require different sets of sensory and sympathetic neurons. Nat Commun. 2012;3:791. doi:10.1038/ncomms1795
  • Nassar MA, Stirling LC, Forlani G, et al. Nociceptor-specific gene deletion reveals a major role for Nav1.7 (PN1) in acute and inflammatory pain. Proc Natl Acad Sci U S A. 2004;101(34):12706–12711. doi:10.1073/pnas.0404915101
  • Shields SD, Cheng X, Uceyler N, Sommer C, Dib-Hajj SD, Waxman SG. Sodium channel Na(v)1.7 is essential for lowering heat pain threshold after burn injury. J Neurosci. 2012;32(32):10819–10832. doi:10.1523/JNEUROSCI.0304-12.2012
  • Minett MS, Falk S, Santana-Varela S, et al. Pain without nociceptors? Nav1.7-independent pain mechanisms. Cell Rep. 2014;6(2):301–312. doi:10.1016/j.celrep.2013.12.033
  • Li Y, North RY, Rhines LD, et al. DRG voltage-gated sodium Channel 1.7 is upregulated in paclitaxel-induced neuropathy in rats and in humans with neuropathic pain. J Neurosci. 2018;38(5):1124–1136. doi:10.1523/JNEUROSCI.0899-17.2017
  • Shields SD, Ahn HS, Yang Y, et al. Nav1.8 expression is not restricted to nociceptors in mouse peripheral nervous system. Pain. 2012;153(10):2017–2030. doi:10.1016/j.pain.2012.04.022
  • He XH, Zang Y, Chen X, et al. TNF-alpha contributes to up-regulation of Nav1.3 and Nav1.8 in DRG neurons following motor fiber injury. Pain. 2010;151:266–279. doi:10.1016/j.pain.2010.06.005
  • Akopian AN, Souslova V, England S, et al. The tetrodotoxin-resistant sodium channel SNS has a specialized function in pain pathways. Nat Neurosci. 1999;2(6):541–548. doi:10.1038/9195
  • Lai J, Gold MS, Kim CS, et al. Inhibition of neuropathic pain by decreased expression of the tetrodotoxin-resistant sodium channel, NaV1.8. Pain. 2002;95(1–2):143–152. doi:10.1016/S0304-3959(01)00391-8
  • Ekberg J, Jayamanne A, Vaughan CW, et al. muO-conotoxin MrVIB selectively blocks Nav1.8 sensory neuron specific sodium channels and chronic pain behavior without motor deficits. ProcNatlAcadSciUSA. 2006;103(45):17030–17035. doi:10.1073/pnas.0601819103
  • Jarvis MF, Honore P, Shieh CC, et al. A-803467, a potent and selective Nav1.8 sodium channel blocker, attenuates neuropathic and inflammatory pain in the rat. Proc Nat Acad Sci. 2007;104(20):8520–8525. doi:10.1073/pnas.0611364104
  • Dib-Hajj SD, Black JA, Waxman SG. NaV1.9: a sodium channel linked to human pain. Nat Rev Neurosci. 2015;16(9):511–519. doi:10.1038/nrn3977
  • Lindia JA, Kohler MG, Martin WJ, Abbadie C. Relationship between sodium channel NaV1.3 expression and neuropathic pain behavior in rats. Pain. 2005;117(1–2):145–153. doi:10.1016/j.pain.2005.05.027
  • Samad OA, Tan AM, Cheng X, Foster E, Dib-Hajj SD, Waxman SG. Virus-mediated shRNA knockdown of Na(v)1.3 in rat dorsal root ganglion attenuates nerve injury-induced neuropathic pain. Mol ther. 2013;21(1):49–56. doi:10.1038/mt.2012.169
  • Tan AM, Samad OA, Dib-Hajj SD, Waxman SG. Virus-mediated knockdown of Nav1.3 in dorsal root ganglia of STZ-induced diabetic rats alleviates tactile allodynia. Mol Med. 2015;21(1):544–552. doi:10.2119/molmed.2015.00063
  • Hains BC, Saab CY, Klein JP, Craner MJ, Waxman SG. Altered sodium channel expression in second-order spinal sensory neurons contributes to pain after peripheral nerve injury. J Neurosci. 2004;24(20):4832–4839. doi:10.1523/JNEUROSCI.0300-04.2004
  • Cheng KI, Wang HC, Tseng KY, et al. Cilostazol ameliorates peripheral neuropathic pain in streptozotocin-induced type I diabetic rats. Front Pharmacol. 2021;12:771271. doi:10.3389/fphar.2021.771271
  • Israel MR, Tanaka BS, Castro J, et al. Na(V) 1.6 regulates excitability of mechanosensitive sensory neurons. J Physiol. 2019;597(14):3751–3768. doi:10.1113/JP278148
  • McDonnell A, Collins S, Ali Z, et al. Efficacy of the Nav1.7 blocker PF-05089771 in a randomised, placebo-controlled, double-blind clinical study in subjects with painful diabetic peripheral neuropathy. Pain. 2018;159(8):1465–1476. doi:10.1097/j.pain.0000000000001227
  • Zakrzewska JM, Palmer J, Morisset V, et al. Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial. Lancet Neurol. 2017;16(4):291–300. doi:10.1016/S1474-4422(17)30005-4
  • Siebenga P, van Amerongen G, Hay JL, et al. Lack of detection of the analgesic properties of PF-05089771, a Selective Na(v) 1.7 inhibitor, using a battery of pain models in healthy subjects. Clin Transl Sci. 2020;13(2):318–324. doi:10.1111/cts.12712
  • Wang W, Gu J, Li YQ, Tao YX. Are voltage-gated sodium channels on the dorsal root ganglion involved in the development of neuropathic pain? Mol Pain. 2011;7:16. doi:10.1186/1744-8069-7-16
  • Priest BT, Kaczorowski GJ. Blocking sodium channels to treat neuropathic pain. Expert Opin Ther Targets. 2007;11(3):291–306. doi:10.1517/14728222.11.3.291
  • Wall PD, Waxman S, Basbaum AI. Ongoing activity in peripheral nerve: injury discharge. Exp Neurol. 1974;45(3):576–589. doi:10.1016/0014-4886(74)90163-0
  • Blumberg H, Janig W. Discharge pattern of afferent fibers from a neuroma. Pain. 1984;20(4):335–353. doi:10.1016/0304-3959(84)90111-8
  • Govrin-Lippmann R, Devor M. Ongoing activity in severed nerves: source and variation with time. Brain Res. 1978;159(2):406–410. doi:10.1016/0006-8993(78)90548-6
  • Li Y, Dorsi MJ, Meyer RA, Belzberg AJ. Mechanical hyperalgesia after an L5 spinal nerve lesion in the rat is not dependent on input from injured nerve fibers. Pain. 2000;85(3):493–502. doi:10.1016/S0304-3959(00)00250-5
  • Michaelis M, Liu XG, Janig W. Axotomized and intact muscle afferents but no skin afferents develop ongoing discharges of dorsal root ganglion origin after peripheral nerve lesion. J Neurosci. 2000;20(7):2742–2748. doi:10.1523/JNEUROSCI.20-07-02742.2000
  • Wu G, Ringkamp M, Hartke TV, et al. Early onset of spontaneous activity in uninjured C-fiber nociceptors after injury to neighboring nerve fibers. J Neurosci. 2001;21(8):RC140. doi:10.1523/JNEUROSCI.21-08-j0002.2001
  • Xu JT, Xin WJ, Wei XH, 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(1):355–365. doi:10.1016/j.expneurol.2006.11.016
  • Obata K, Yamanaka H, Kobayashi K, et al. The effect of site and type of nerve injury on the expression of brain-derived neurotrophic factor in the dorsal root ganglion and on neuropathic pain behavior. Neuroscience. 2006;137(3):961–970. doi:10.1016/j.neuroscience.2005.10.015
  • Black JA, Cummins TR, Plumpton C, et al. Upregulation of a silent sodium channel after peripheral, but not central, nerve injury in DRG neurons. JNeurophysiol. 1999;82(5):2776–2785. doi:10.1152/jn.1999.82.5.2776
  • Sheen K, Chung JM. Signs of neuropathic pain depend on signals from injured nerve fibers in a rat model. Brain Res. 1993;610(1):62–68. doi:10.1016/0006-8993(93)91217-G
  • Luo ZD, Chaplan SR, Higuera ES, et al. Upregulation of dorsal root ganglion (alpha)2(delta) calcium channel subunit and its correlation with allodynia in spinal nerve-injured rats. J Neurosci. 2001;21(6):1868–1875. doi:10.1523/JNEUROSCI.21-06-01868.2001
  • Liu XG, Pang RP, Zhou LJ, Wei XH, Zang Y. Neuropathic pain: sensory nerve injury or motor nerve injury? Adv Exp Med Biol. 2016;904:59–75.
  • Tamura R, Nemoto T, Maruta T, et al. Up-regulation of NaV1.7 sodium channels expression by tumor necrosis factor-alpha in cultured bovine adrenal chromaffin cells and rat dorsal root ganglion neurons. Anesth Analg. 2014;118(2):318–324. doi:10.1213/ANE.0000000000000085
  • Noh MC, Stemkowski PL, Smith PA. Long-term actions of interleukin-1β on K(+), Na(+) and Ca(2+) channel currents in small, IB(4)-positive dorsal root ganglion neurons; possible relevance to the etiology of neuropathic pain. J Neuroimmunol. 2019;332:198–211. doi:10.1016/j.jneuroim.2019.05.002
  • Binshtok AM, Wang H, Zimmermann K, et al. Nociceptors are interleukin-1beta sensors. J Neurosci. 2008;28(52):14062–14073. doi:10.1523/JNEUROSCI.3795-08.2008
  • Goldstein RH, Barkai O, Íñigo-portugués A, Katz B, Lev S, Binshtok AM. Location and plasticity of the sodium spike initiation zone in nociceptive terminals in vivo. Neuron. 2019;102(4):801–812.e805. doi:10.1016/j.neuron.2019.03.005
  • Liu L, Yang TM, Liedtke W, Simon SA. Chronic IL-1beta signaling potentiates voltage-dependent sodium currents in trigeminal nociceptive neurons. J Neurophysiol. 2006;95(3):1478–1490. doi:10.1152/jn.00509.2005
  • Milligan ED, Penzkover KR, Soderquist RG, Mahoney MJ. Spinal interleukin-10 therapy to treat peripheral neuropathic pain. Neuromodulation. 2012;15(6):520–526; discussion 526. doi:10.1111/j.1525-1403.2012.00462.x
  • Shen KF, Zhu HQ, Wei XH, et al. Interleukin-10 down-regulates voltage gated sodium channels in rat dorsal root ganglion neurons. Exp Neurol. 2013;247:466–475. doi:10.1016/j.expneurol.2013.01.018
  • Huang Y, Zhu L, Zhang W, Tang Q, Zhong Y. IL-10 alleviates radicular pain by inhibiting TNF-α/p65 dependent Nav1.7 up-regulation in DRG neurons of rats. Brain Res. 2022;1791:147997. doi:10.1016/j.brainres.2022.147997
  • Meffert MK, Baltimore D. Physiological functions for brain NF-kappaB. Trends Neurosci. 2005;28(1):37–43. doi:10.1016/j.tins.2004.11.002
  • Taniguchi K, Karin M. NF-kappaB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18(5):309–324. doi:10.1038/nri.2017.142
  • Srinivasan M, Lahiri DK. Significance of NF-kappaB as a pivotal therapeutic target in the neurodegenerative pathologies of Alzheimer’s disease and multiple sclerosis. Expert Opin Ther Targets. 2015;19(4):471–487. doi:10.1517/14728222.2014.989834
  • Niederberger E, Geisslinger G. The IKK-NF-kappaB pathway: a source for novel molecular drug targets in pain therapy? FASEB J. 2008;22(10):3432–3442. doi:10.1096/fj.08-109355
  • Zang Y, He XH, Xin WJ, et al. Inhibition of NF-kappaB prevents mechanical allodynia induced by spinal ventral root transection and suppresses the re-expression of Nav1.3 in DRG neurons in vivo and in vitro. Brain Res. 2010;1363:151–158. doi:10.1016/j.brainres.2010.09.048
  • Huang Y, Zang Y, Zhou L, Gui W, Liu X, Zhong Y. The role of TNF-alpha/NF-kappa B pathway on the up-regulation of voltage-gated sodium channel Nav1.7 in DRG neurons of rats with diabetic neuropathy. Neurochem Int. 2014;75:112–119. doi:10.1016/j.neuint.2014.05.012
  • Zhang JM, Li H, Liu B, Brull SJ. Acute topical application of tumor necrosis factor alpha evokes protein kinase A-dependent responses in rat sensory neurons. JNeurophysiol. 2002;88(3):1387–1392. doi:10.1152/jn.2002.88.3.1387
  • Xie MX, Zhang XL, Xu J, et al. Nuclear Factor-kappaB gates Nav1.7 channels in DRG neurons via protein-protein interaction. iScience. 2019;19:623–633. doi:10.1016/j.isci.2019.08.017
  • Zhang XL, Lai RC, Chen ZH, et al. Foxo1 selectively regulates static mechanical pain by interacting with Nav1.7. Pain. 2021;162(2):490–502. doi:10.1097/j.pain.0000000000002055
  • Shi C, Shi R, Guo H. Tumor necrosis factor α reduces gonadotropin-releasing hormone release through increase of forkhead box protein O1 activity. Neuroreport. 2020;31(6):473–477. doi:10.1097/WNR.0000000000001424
  • Dolphin AC. Calcium channel auxiliary alpha2delta and beta subunits: trafficking and one step beyond. Nat Rev Neurosci. 2012;13(8):542–555. doi:10.1038/nrn3311
  • Cai S, Gomez K, Moutal A, Khanna R. Targeting T-type/CaV3.2 channels for chronic pain. Transl Res. 2021;234:20–30. doi:10.1016/j.trsl.2021.01.002
  • Liu QY, Chen W, Cui S, et al. Upregulation of Ca(v)3.2 T-type calcium channels in adjacent intact L4 dorsal root ganglion neurons in neuropathic pain rats with L5 spinal nerve ligation. Neurosci Res. 2019;142:30–37. doi:10.1016/j.neures.2018.04.002
  • Dubel SJ, Starr TV, Hell J, et al. Molecular cloning of the alpha-1 subunit of an omega-conotoxin-sensitive calcium channel. Proc Natl Acad Sci U S A. 1992;89(11):5058–5062. doi:10.1073/pnas.89.11.5058
  • Field MJ, Cox PJ, Stott E, et al. Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci U S A. 2006;103(46):17537–17542. doi:10.1073/pnas.0409066103
  • Skov MJ, Beck JC, de Kater AW, Shopp GM. Nonclinical safety of ziconotide: an intrathecal analgesic of a new pharmaceutical class. Int J Toxicol. 2007;26(5):411–421. doi:10.1080/10915810701582970
  • Snutch TP. Targeting chronic and neuropathic pain: the N-type calcium channel comes of age. NeuroRx. 2005;2(4):662–670. doi:10.1602/neurorx.2.4.662
  • Liu Q, Chen W, Fan X, et al. Upregulation of interleukin-6 on Ca(v)3.2 T-type calcium channels in dorsal root ganglion neurons contributes to neuropathic pain in rats with spinal nerve ligation. Exp Neurol. 2019;317:226–243. doi:10.1016/j.expneurol.2019.03.005
  • Brown DA, Passmore GM. Neural KCNQ (Kv7) channels. Br J Pharmacol. 2009;156(8):1185–1195. doi:10.1111/j.1476-5381.2009.00111.x
  • Liu Y, Bian X, Wang K. Pharmacological activation of neuronal voltage-gated Kv7/KCNQ/M-channels for potential therapy of epilepsy and pain. Handb Exp Pharmacol. 2021;267:231–251.
  • Ibeakanma C, Vanner S. TNFalpha is a key mediator of the pronociceptive effects of mucosal supernatant from human ulcerative colitis on colonic DRG neurons. Gut. 2010;59(5):612–621. doi:10.1136/gut.2009.190439
  • Stemkowski PL, Noh MC, Chen Y, Smith PA. Increased excitability of medium-sized dorsal root ganglion neurons by prolonged interleukin-1β exposure is K(+) channel dependent and reversible. J Physiol. 2015;593(16):3739–3755. doi:10.1113/JP270905
  • Stemkowski PL, Bukhanova-Schulz N, Baldwin T, de Chaves EP, Smith PA. Are sensory neurons exquisitely sensitive to interleukin 1β? J Neuroimmunol. 2021;354:577529. doi:10.1016/j.jneuroim.2021.577529
  • Moran MM, Szallasi A. Targeting nociceptive transient receptor potential channels to treat chronic pain: current state of the field. Br J Pharmacol. 2018;175(12):2185–2203. doi:10.1111/bph.14044
  • Rosenbaum T, Simon SA. Frontiers in neuroscience TRPV1 receptors and signal transduction. In: Liedtke WB, Heller S, editors. TRP Ion Channel Function in Sensory Transduction and Cellular Signaling Cascades. Boca Raton (FL): CRC Press/Taylor & Francis Copyright © 2007, Taylor & Francis Group, LLC.; 2007.
  • Hu F, Song X, Long D. Transient receptor potential ankyrin 1 and calcium: interactions and association with disease (Review). Exp Ther Med. 2021;22(6):1462. doi:10.3892/etm.2021.10897
  • Ji G, Zhou S, Carlton SM. Intact Adelta-fibers up-regulate transient receptor potential A1 and contribute to cold hypersensitivity in neuropathic rats. Neuroscience. 2008;154(3):1054–1066. doi:10.1016/j.neuroscience.2008.04.039
  • Wang Z, Ling D, Wu C, Han J, Zhao Y. Baicalin prevents the up-regulation of TRPV1 in dorsal root ganglion and attenuates chronic neuropathic pain. Veter med sci. 2020;6(4):1034–1040. doi:10.1002/vms3.318
  • Hara T, Chiba T, Abe K, et al. Effect of paclitaxel on transient receptor potential vanilloid 1 in rat dorsal root ganglion. Pain. 2013;154(6):882–889. doi:10.1016/j.pain.2013.02.023
  • Ba X, Wang J, Zhou S, et al. Cinobufacini protects against paclitaxel-induced peripheral neuropathic pain and suppresses TRPV1 up-regulation and spinal astrocyte activation in rats. Biomed Pharmacother. 2018;108:76–84. doi:10.1016/j.biopha.2018.09.018
  • Iftinca M, Defaye M, Altier C. TRPV1-targeted drugs in development for human pain conditions. Drugs. 2021;81(1):7–27. doi:10.1007/s40265-020-01429-2
  • Wang Y, Feng C, He H, et al. Sensitization of TRPV1 receptors by TNF-α orchestrates the development of vincristine-induced pain. Oncol Lett. 2018;15(4):5013–5019. doi:10.3892/ol.2018.7986
  • Leo M, Schulte M, Schmitt LI, Schäfers M, Kleinschnitz C, Hagenacker T. Intrathecal resiniferatoxin modulates TRPV1 in DRG neurons and reduces TNF-induced pain-related behavior. Mediators Inflamm. 2017;2017:2786427. doi:10.1155/2017/2786427
  • Malek N, Pajak A, Kolosowska N, Kucharczyk M, Starowicz K. The importance of TRPV1-sensitisation factors for the development of neuropathic pain. Mol Cell Neurosci. 2015;65:1–10. doi:10.1016/j.mcn.2015.02.001
  • Hensellek S, Brell P, Schaible HG, Bräuer R, Segond von Banchet G. Segond von Banchet G: the cytokine TNFalpha increases the proportion of DRG neurones expressing the TRPV1 receptor via the TNFR1 receptor and ERK activation. Mol Cell Neurosci. 2007;36(3):381–391. doi:10.1016/j.mcn.2007.07.010
  • Nugent M, Yusef YR, Meng J, Wang J, Dolly JO. A SNAP-25 cleaving chimera of botulinum neurotoxin /A and /E prevents TNFα-induced elevation of the activities of native TRP channels on early postnatal rat dorsal root ganglion neurons. Neuropharmacology. 2018;138:257–266. doi:10.1016/j.neuropharm.2018.06.016
  • Zhao D, Han DF, Wang SS, Lv B, Wang X, Ma C. Roles of tumor necrosis factor-α and interleukin-6 in regulating bone cancer pain via TRPA1 signal pathway and beneficial effects of inhibition of neuro-inflammation and TRPA1. Mol Pain. 2019;15:1744806919857981. doi:10.1177/1744806919857981
  • El Karim I, McCrudden MT, Linden GJ, et al. TNF-α-induced p38MAPK activation regulates TRPA1 and TRPV4 activity in odontoblast-like cells. Am J Pathol. 2015;185(11):2994–3002. doi:10.1016/j.ajpath.2015.07.020
  • Wu Z, Wang S, Wu I, Mata M, Fink DJ. Activation of TLR-4 to produce tumour necrosis factor-α in neuropathic pain caused by paclitaxel. Eur J Pain. 2015;19(7):889–898. doi:10.1002/ejp.613
  • Ebbinghaus M, Uhlig B, Richter F, et al. The role of interleukin-1β in arthritic pain: main involvement in thermal, but not mechanical, hyperalgesia in rat antigen-induced arthritis. Arthritis Rheum. 2012;64(12):3897–3907. doi:10.1002/art.34675
  • Araldi D, Ferrari LF, Lotufo CM, et al. Peripheral inflammatory hyperalgesia depends on the COX increase in the dorsal root ganglion. Proc Natl Acad Sci U S A. 2013;110(9):3603–3608. doi:10.1073/pnas.1220668110
  • Zhang J, Yi QT, Gong M, Zhang YQ, Liu D, Zhu RJ. Upregulation of TRPV1 in spinal dorsal root ganglion by activating NGF-TrkA pathway contributes to pelvic organ cross-sensitisation in rats with experimental autoimmune prostatitis. Andrologia. 2019;51(8):e13302. doi:10.1111/and.13302
  • Amirkhanloo F, Karimi G, Yousefi-Manesh H, Abdollahi A, Roohbakhsh A, Dehpour AR. The protective effect of modafinil on vincristine-induced peripheral neuropathy in rats: a possible role for TRPA1 receptors. Basic Clin Pharmacol Toxicol. 2020;127(5):405–418. doi:10.1111/bcpt.13454
  • Waldmann R, Champigny G, Bassilana F, Heurteaux C, Lazdunski M. A proton-gated cation channel involved in acid-sensing. Nature. 1997;386(6621):173–177. doi:10.1038/386173a0
  • Papalampropoulou-Tsiridou M, Labrecque S, Godin AG, De Koninck Y, Wang F. Differential expression of acid - sensing ion channels in mouse primary afferents in naïve and injured conditions. Front Cell Neurosci. 2020;14:103. doi:10.3389/fncel.2020.00103
  • Diochot S, Alloui A, Rodrigues P, et al. Analgesic effects of mambalgin peptide inhibitors of acid-sensing ion channels in inflammatory and neuropathic pain. Pain. 2016;157(3):552–559. doi:10.1097/j.pain.0000000000000397
  • Deval E, Gasull X, Noël J, et al. Acid-sensing ion channels (ASICs): pharmacology and implication in pain. Pharmacol Ther. 2010;128(3):549–558. doi:10.1016/j.pharmthera.2010.08.006
  • Kung CC, Huang YC, Hung TY, Teng CY, Lee TY, Sun WH. Deletion of acid-sensing ion channel 3 relieves the late phase of neuropathic pain by preventing neuron degeneration and promoting neuron repair. Cells. 2020;9(11):2355. doi:10.3390/cells9112355
  • Wei S, Qiu CY, Jin Y, Liu TT, Hu WP. TNF-α acutely enhances acid-sensing ion channel currents in rat dorsal root ganglion neurons via a p38 MAPK pathway. J Neuroinflammation. 2021;18(1):92. doi:10.1186/s12974-021-02151-w
  • Verkest C, Diochot S, Lingueglia E, Baron A. C-Jun N-terminal kinase post-translational regulation of pain-related acid-sensing ion channels 1b and 3. J Neurosci. 2021;41(42):8673–8685. doi:10.1523/JNEUROSCI.0570-21.2021
  • Gong W, Kolker SJ, Usachev Y, et al. Acid-sensing ion channel 3 decreases phosphorylation of extracellular signal-regulated kinases and induces synoviocyte cell death by increasing intracellular calcium. Arthritis Res Ther. 2014;16(3):R121. doi:10.1186/ar4577
  • Ross JL, Queme LF, Cohen ER, et al. Muscle IL1β drives ischemic myalgia via ASIC3-mediated sensory neuron sensitization. J Neurosci. 2016;36(26):6857–6871. doi:10.1523/JNEUROSCI.4582-15.2016
  • Ross JL, Queme LF, Lamb JE, Green KJ, Ford ZK, Jankowski MP. Interleukin 1β inhibition contributes to the antinociceptive effects of voluntary exercise on ischemia/reperfusion-induced hypersensitivity. Pain. 2018;159(2):380–392. doi:10.1097/j.pain.0000000000001094
  • Bliss TV, Lomo T. Long-lasting potentiation of synaptic transmission in the dentate area of the anaesthetized rabbit following stimulation of the perforant path. J Physiol. 1973;232(2):331–356. doi:10.1113/jphysiol.1973.sp010273
  • Liu XG, Sandkuhler J. Long-term potentiation of C-fiber-evoked potentials in the rat spinal dorsal horn is prevented by spinal N-methyl-D-aspartic acid receptor blockage. Neurosci Lett. 1995;191(1–2):43–46. doi:10.1016/0304-3940(95)11553-0
  • Gobel S, Falls WM. Anatomical observations of horseradish peroxidase-filled terminal primary axonal arborizations in layer II of the substantia gelatinosa of Rolando. Brain Res. 1979;175(2):335–340. doi:10.1016/0006-8993(79)91012-6
  • Light AR, Trevino DL, Perl ER. Morphological features of functionally defined neurons in the marginal zone and substantia gelatinosa of the spinal dorsal horn. J Comp Neurol. 1979;186(2):151–171. doi:10.1002/cne.901860204
  • Liu XG, Sandkuhler J. Characterization of long-term potentiation of C-fiber-evoked potentials in spinal dorsal horn of adult rat: essential role of NK1 and NK2 receptors. J Neurophysiol. 1997;78(4):1973–1982. doi:10.1152/jn.1997.78.4.1973
  • Ikeda H, Stark J, Fischer H, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science. 2006;312(5780):1659–1662. doi:10.1126/science.1127233
  • Sandkuhler J, Liu XG. Induction of long-term potentiation at spinal synapses by noxious stimulation or nerve injury. Eur J Neurosci. 1998;10(7):2476–2480. doi:10.1046/j.1460-9568.1998.00278.x
  • Zhang HM, Zhou LJ, Hu XD, Hu NW, Zhang T, Liu XG. Acute nerve injury induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn of intact rat. Sheng Li XueBao. 2004;56(5):591–596.
  • Zhou LJ, Ren WJ, Zhong Y, et al. Limited BDNF contributes to the failure of injury to skin afferents to produce a neuropathic pain condition. Pain. 2010;148(1):148–157. doi:10.1016/j.pain.2009.10.032
  • Drdla R, Gassner M, Gingl E, Sandkuhler J. Induction of synaptic long-term potentiation after opioid withdrawal. Science. 2009;325(5937):207–210. doi:10.1126/science.1171759
  • Klein T, Magerl W, Hopf HC, Sandkuhler J, Treede RD. Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci. 2004;24(4):964–971. doi:10.1523/JNEUROSCI.1222-03.2004
  • Ohnami S, Tanabe M, Shinohara S, Takasu K, Kato A, Ono H. Role of voltage-dependent calcium channel subtypes in spinal long-term potentiation of C-fiber-evoked field potentials. Pain. 2011;152(3):623–631. doi:10.1016/j.pain.2010.12.004
  • Tanabe M, Murakami H, Honda M, Ono H. Gabapentin depresses C-fiber-evoked field potentials in rat spinal dorsal horn only after induction of long-term potentiation. ExpNeurol. 2006;202(2):280–286.
  • Ge YX, Xin WJ, Hu NW, Zhang T, Xu JT, Liu XG. Clonidine depresses LTP of C-fiber evoked field potentials in spinal dorsal horn via NO-cGMP pathway. Brain Res. 2006;1118:58–65. doi:10.1016/j.brainres.2006.08.009
  • Zhang HM, Zhou LJ, Hu NW, Zhang T, Liu XG. NMDA receptor channels are involved in the expression of long-term potentiation of C-fiber evoked field potentials in rat spinal dorsal horn. Prog Biochem Biophy. 2006;33(12):1183–1189.
  • Hu XD, Ge YX, Hu NW, et al. Diazepam inhibits the induction and maintenance of LTP of C-fiber evoked field potentials in spinal dorsal horn of rats. Neuropharmacology. 2006;50(2):238–244. doi:10.1016/j.neuropharm.2005.09.010
  • Heinricher MM, Tavares I, Leith JL, Lumb BM. Descending control of nociception: specificity, recruitment and plasticity. Brain ResRev. 2009;60(1):214–225. doi:10.1016/j.brainresrev.2008.12.009
  • Liu XG, Morton CR, Azkue JJ, Zimmermann M, Sandkuhler J. Long-term depression of C-fibre-evoked spinal field potentials by stimulation of primary afferent A delta-fibres in the adult rat. EurJNeurosci. 1998;10(10):3069–3075.
  • Wood PB. Role of central dopamine in pain and analgesia. ExpertRevNeurother. 2008;8(5):781–797.
  • Pertovaara A. Noradrenergic pain modulation. ProgNeurobiol. 2006;80(2):53–83.
  • Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic ClinPharmacolToxicol. 2005;96(6):399–409.
  • Shelton RC. Serotonin and norepinephrine reuptake inhibitors. Handb Exp Pharmacol. 2019;250:145–180.
  • Yang HW, Zhou LJ, Hu NW, Xin WJ, Liu XG. Activation of spinal D1/D5 receptors induces late-phase LTP of C-fiber-evoked field potentials in rat spinal dorsal horn. J Neurophysiol. 2005;94(2):961–967. doi:10.1152/jn.01324.2004
  • Zhu H, Clemens S, Sawchuk M, Hochman S. Expression and distribution of all dopamine receptor subtypes (D(1)-D(5)) in the mouse lumbar spinal cord: a real-time polymerase chain reaction and non-autoradiographic in situ hybridization study. Neuroscience. 2007;149(4):885–897. doi:10.1016/j.neuroscience.2007.07.052
  • Kim JY, Tillu DV, Quinn TL, et al. Spinal dopaminergic projections control the transition to pathological pain plasticity via a D1/D5-mediated mechanism. J Neurosci. 2015;35(16):6307–6317. doi:10.1523/JNEUROSCI.3481-14.2015
  • Megat S, Shiers S, Moy JK, et al. A critical role for dopamine d5 receptors in pain chronicity in male mice. J Neurosci. 2018;38(2):379–397. doi:10.1523/JNEUROSCI.2110-17.2017
  • Pickering M, Cumiskey D, O’Connor JJ. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. ExpPhysiol. 2005;90(5):663–670.
  • Katsuki H, Nakai S, Hirai Y, Akaji K, Kiso Y, Satoh M. Interleukin-1 beta inhibits long-term potentiation in the CA3 region of mouse hippocampal slices. Eur J Pharmacol. 1990;181(3):323–326. doi:10.1016/0014-2999(90)90099-R
  • Pickering M, O’Connor JJ. Pro-inflammatory cytokines and their effects in the dentate gyrus. In: Helen ES, editor. Progress in Brain Research the Dentate Gyrus: A Comprehensive Guide to Structure, Function, and Clinical Implications. Vol. 163. Elsevier; 2007:339–354.
  • Butler MP, O’Connor JJ, Moynagh PN. Dissection of tumor-necrosis factor-alpha inhibition of long-term potentiation (LTP) reveals a p38 mitogen-activated protein kinase-dependent mechanism which maps to early-but not late-phase LTP. Neuroscience. 2004;124(2):319–326. doi:10.1016/j.neuroscience.2003.11.040
  • Wang Q, Walsh DM, Rowan MJ, Selkoe DJ, Anwyl R. Block of long-term potentiation by naturally secreted and synthetic amyloid beta-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5. J Neurosci. 2004;24(13):3370–3378. doi:10.1523/JNEUROSCI.1633-03.2004
  • Zhong Y, Zhou LJ, Ren WJ, et al. Interleukin-1beta induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn in rats with neuropathic pain. Open Pain J. 2009;2:18–23. doi:10.2174/1876386300902010018
  • Liu YL, Zhou LJ, Hu NW, 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(3):708–715. doi:10.1016/j.neuropharm.2006.09.011
  • Zhong Y, Zhou LJ, Ren WJ, et al. The direction of synaptic plasticity mediated by C-fibers in spinal dorsal horn is decided by Src-family kinases in microglia: the role of tumor necrosis factor-alpha. Brain BehavImmun. 2010;24:874–880.
  • Cowley TR, O’Sullivan J, Blau C, et al. Rosiglitazone attenuates the age-related changes in astrocytosis and the deficit in LTP. Neurobiol Aging. 2012;33(1):162–175. doi:10.1016/j.neurobiolaging.2010.02.002
  • Griffin R, Nally R, Nolan Y, McCartney Y, Linden J, Lynch MA. The age-related attenuation in long-term potentiation is associated with microglial activation. J Neurochem. 2006;99(4):1263–1272. doi:10.1111/j.1471-4159.2006.04165.x
  • Hayashi Y, Yoshida M, Yamato M, et al. Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice. J Neurosci. 2008;28(34):8624–8634. doi:10.1523/JNEUROSCI.1957-08.2008
  • VanItallie TB. Alzheimer’s disease: innate immunity gone awry? Metabolism. 2017;69s:S41–s49. doi:10.1016/j.metabol.2017.01.014
  • 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
  • Gong QJ, Li YY, Xin WJ, et al. ATP induces long-term potentiation of C-fiber-evoked field potentials in spinal dorsal horn: the roles of P2X(4) receptors and p38 MAPK in microglia. Glia. 2009;57:583–591. doi:10.1002/glia.20786
  • Zhou LJ, Yang T, Wei XA, et al. Brain-derived neurotrophic factor contributes to spinal long-term potentiation and mechanical hypersensitivity by activation of spinal microglia in rat. Brain Behav Immun. 2011;25(2):322–334. doi:10.1016/j.bbi.2010.09.025
  • Kronschlager MT, Drdla-Schutting R, Gassner M, Honsek SD, Teuchmann HL, Sandkuhler J. Gliogenic LTP spreads widely in nociceptive pathways. Science. 2016;354(6316):1144–1148. doi:10.1126/science.aah5715
  • Zhou LJ, Liu XG. Glial activation, A common mechanism underlying spinal synaptic plasticity? Neurosci Bull. 2017;33(1):121–123. doi:10.1007/s12264-016-0091-0
  • Zhou LJ, Zhong Y, Ren WJ, Li YY, Zhang T, Liu XG. BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. ExpNeurol. 2008;212(2):507–514.
  • Yang HW, Hu XD, Zhang HM, et al. The roles of CaMKII, PKA and PKC in the induction and maintenance of LTP of C-fiber evoked field potentials in rat spinal dorsal horn. JNeurophysiol. 2004;91(3):1122–1133. doi:10.1152/jn.00735.2003
  • Xin WJ, Gong QJ, Xu JT, et al. Role of phosphorylation of ERK in induction and maintenance of LTP of the C-fiber evoked field potentials in spinal dorsal horn. J NeurosciRes. 2006;84(5):934–943.
  • Sorra KE, Harris KM. Overview on the structure, composition, function, development, and plasticity of hippocampal dendritic spines. Hippocampus. 2000;10(5):501–511. doi:10.1002/1098-1063(2000)10:5<501::AID-HIPO1>3.0.CO;2-T
  • Zhang HM, Li Y, Yang Q, Liu XG, Dougherty PM. Morphological and physiological plasticity of spinal lamina II GABA neurons is induced by sciatic nerve chronic constriction injury in mice. Front Cell Neurosci. 2018;12:143. doi:10.3389/fncel.2018.00143
  • Tyrtyshnaia A, Bondar A, Konovalova S, Manzhulo I. Synaptamide improves cognitive functions and neuronal plasticity in neuropathic pain. Int J Mol Sci. 2021;22(23):12779. doi:10.3390/ijms222312779
  • Cardoso-Cruz H, Dourado M, Monteiro C, Matos MR, Galhardo V. Activation of dopaminergic D2/D3 receptors modulates dorsoventral connectivity in the hippocampus and reverses the impairment of working memory after nerve injury. J Neurosci. 2014;34(17):5861–5873. doi:10.1523/JNEUROSCI.0021-14.2014
  • Fonseca-Rodrigues D, Amorim D, Almeida A, Pinto-Ribeiro F. Emotional and cognitive impairments in the peripheral nerve chronic constriction injury model (CCI) of neuropathic pain: a systematic review. Behav Brain Res. 2021;399:113008. doi:10.1016/j.bbr.2020.113008
  • Xiong B, Zhang W, Zhang L, et al. Hippocampal glutamatergic synapses impairment mediated novel-object recognition dysfunction in rats with neuropathic pain. Pain. 2020;161(8):1824–1836. doi:10.1097/j.pain.0000000000001878
  • Mutso AA, Radzicki D, Baliki MN, et al. Abnormalities in hippocampal functioning with persistent pain. J Neurosci. 2012;32(17):5747–5756. doi:10.1523/JNEUROSCI.0587-12.2012
  • Cardoso-Cruz H, Lima D, Galhardo V. Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus-prefrontal cortex connectivity. J Neurosci. 2013;33(6):2465–2480. doi:10.1523/JNEUROSCI.5197-12.2013
  • Messaoudi E, Ying SW, Kanhema T, Croll SD, Bramham CR. Brain-derived neurotrophic factor triggers transcription-dependent, late phase long-term potentiation in vivo. J Neurosci. 2002;22(17):7453–7461. doi:10.1523/JNEUROSCI.22-17-07453.2002
  • Geng SJ, Liao FF, Dang WH, et al. Contribution of the spinal cord BDNF to the development of neuropathic pain by activation of the NR2B-containing NMDA receptors in rats with spinal nerve ligation. ExpNeurol. 2010;222(2):256–266.
  • Zhou W, Xie Z, Li C, et al. Driving effect of BDNF in the spinal dorsal horn on neuropathic pain. Neurosci Lett. 2021;756:135965. doi:10.1016/j.neulet.2021.135965
  • Mai CL, Wei X, Gui WS, et al. Differential regulation of GSK-3beta in spinal dorsal horn and in hippocampus mediated by interleukin-1beta contributes to pain hypersensitivity and memory deficits following peripheral nerve injury. Mol Pain. 2019;15:1744806919826789. doi:10.1177/1744806919826789
  • Xue M, Sun YL, Xia YY, Huang ZH, Huang C, Xing GG. Electroacupuncture modulates spinal BDNF/TrκB signaling pathway and ameliorates the sensitization of dorsal horn WDR neurons in spared nerve injury rats. Int J Mol Sci. 2020;21(18):6524. doi:10.3390/ijms21186524
  • Park H, Poo MM. Neurotrophin regulation of neural circuit development and function. Nat Rev Neurosci. 2013;14(1):7–23. doi:10.1038/nrn3379
  • Jia D, Gao GD, Liu Y, et al. TNF-alpha involves in altered prefrontal synaptic transmission in mice with persistent inflammatory pain. Neurosci Lett. 2007;415(1):1–5. doi:10.1016/j.neulet.2006.12.032
  • Yao PW, Wang SK, Chen SX, Xin WJ, Liu XG, Zang Y. Upregulation of tumor necrosis factor-alpha in the anterior cingulate cortex contributes to neuropathic pain and pain-associated aversion. Neurobiol Dis. 2019;130:104456. doi:10.1016/j.nbd.2019.04.012
  • 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 behavioural changes. Neuroscience. 2019;416:147–167. doi:10.1016/j.neuroscience.2019.08.005
  • Nascimento FP, Macedo-Júnior SJ, Borges FR, et al. Thalidomide reduces mechanical hyperalgesia and depressive-like behavior induced by peripheral nerve crush in mice. Neuroscience. 2015;303:51–58. doi:10.1016/j.neuroscience.2015.06.044
  • Zigmond RE, Echevarria FD. Macrophage biology in the peripheral nervous system after injury. Prog Neurobiol. 2019;173:102–121. doi:10.1016/j.pneurobio.2018.12.001
  • Yu X, Basbaum A, Guan Z. Contribution of colony-stimulating factor 1 to neuropathic pain. Pain Rep. 2021;6(1):e883. doi:10.1097/PR9.0000000000000883
  • Echeverry S, Shi XQ, Rivest S, Zhang J. Peripheral nerve injury alters blood-spinal cord barrier functional and molecular integrity through a selective inflammatory pathway. J Neurosci. 2011;31(30):10819–10828. doi:10.1523/JNEUROSCI.1642-11.2011
  • Zhang J, Shi XQ, Echeverry S, Mogil JS, De Koninck Y, Rivest S. Expression of CCR2 in both resident and bone marrow-derived microglia plays a critical role in neuropathic pain. J Neurosci. 2007;27(45):12396–12406. doi:10.1523/JNEUROSCI.3016-07.2007
  • Prinz M, Priller J, Sisodia SS, Ransohoff RM. Heterogeneity of CNS myeloid cells and their roles in neurodegeneration. Nat Neurosci. 2011;14(10):1227–1235. doi:10.1038/nn.2923
  • Fife BT, Huffnagle GB, Kuziel WA, Karpus WJ. CC chemokine receptor 2 is critical for induction of experimental autoimmune encephalomyelitis. J Exp Med. 2000;192(6):899–905. doi:10.1084/jem.192.6.899
  • Fang W, Zhai X, Han D, et al. CCR2-dependent monocytes/macrophages exacerbate acute brain injury but promote functional recovery after ischemic stroke in mice. Theranostics. 2018;8(13):3530–3543. doi:10.7150/thno.24475
  • Mai CL, Tan Z, Xu YN, et al. CXCL12-mediated monocyte transmigration into brain perivascular space leads to neuroinflammation and memory deficit in neuropathic pain. Theranostics. 2021;11(3):1059–1078. doi:10.7150/thno.44364
  • Donnelly CR, Andriessen AS, Chen G, et al. Central nervous system targets: glial cell mechanisms in chronic pain. Neurotherapeutics. 2020;17(3):846–860. doi:10.1007/s13311-020-00905-7
  • Hanani M, Spray DC. Emerging importance of satellite glia in nervous system function and dysfunction. Nat Rev Neurosci. 2020;21(9):485–498. doi:10.1038/s41583-020-0333-z
  • Grace PM, Hutchinson MR, Maier SF, Watkins LR. Pathological pain and the neuroimmune interface. Nat Rev Immunol. 2014;14(4):217–231. doi:10.1038/nri3621
  • Regen F, Hellmann-Regen J, Costantini E, Reale M. Neuroinflammation and Alzheimer’s disease: implications for microglial activation. Curr Alzheimer Res. 2017;14(11):1140–1148. doi:10.2174/1567205014666170203141717
  • Santos LE, Beckman D, Ferreira ST. Microglial dysfunction connects depression and Alzheimer’s disease. Brain Behav Immun. 2016;55:151–165. doi:10.1016/j.bbi.2015.11.011
  • Liu Y, Yin Y. Emerging roles of immune cells in postoperative cognitive dysfunction. Mediators Inflamm. 2018;2018:6215350. doi:10.1155/2018/6215350
  • Yang CP, Cherng CH, Wu CT, et al. Intrathecal ultra-low dose naloxone enhances the antihyperalgesic effects of morphine and attenuates tumor necrosis factor-α and tumor necrosis factor-α receptor 1 expression in the dorsal horn of rats with partial sciatic nerve transection. Anesth Analg. 2013;117(6):1493–1502. doi:10.1213/ANE.0000000000000020
  • Wang J, Liu Y, Zhou LJ, et al. Magnesium L-threonate prevents and restores memory deficits associated with neuropathic pain by inhibition of TNF-alpha. Pain Phys. 2013;16(5):E563–575.
  • Lawrence T. The nuclear factor NF-kappaB pathway in inflammation. Cold Spring Harb Perspect Biol. 2009;1(6):a001651. doi:10.1101/cshperspect.a001651
  • Pollock G, Pennypacker KR, Mémet S, Israël A, Saporta S. Activation of NF-kappaB in the mouse spinal cord following sciatic nerve transection. Exp Brain Res. 2005;165(4):470–477. doi:10.1007/s00221-005-2318-6
  • Möser CV, Kynast K, Baatz K, et al. The protein kinase IKKε is a potential target for the treatment of inflammatory hyperalgesia. J Immunol. 2011;187(5):2617–2625. doi:10.4049/jimmunol.1004088
  • Kanngiesser M, Häussler A, Myrczek T, et al. Inhibitor kappa B kinase beta dependent cytokine upregulation in nociceptive neurons contributes to nociceptive hypersensitivity after sciatic nerve injury. J Pain. 2012;13(5):485–497. doi:10.1016/j.jpain.2012.02.010
  • Niu YL, Guo Z, Zhou RH. Up-regulation of TNF-alpha in neurons of dorsal root ganglia and spinal cord during coronary artery occlusion in rats. Cytokine. 2009;47(1):23–29. doi:10.1016/j.cyto.2009.04.003
  • Gruber-Schoffnegger D, Drdla-Schutting R, Hönigsperger C, Wunderbaldinger G, Gassner M, Sandkühler J. Induction of thermal hyperalgesia and synaptic long-term potentiation in the spinal cord lamina I by TNF-α and IL-1β is mediated by glial cells. J Neurosci. 2013;33(15):6540–6551. doi:10.1523/JNEUROSCI.5087-12.2013
  • Brás JP, Bravo J, Freitas J, et al. TNF-alpha-induced microglia activation requires miR-342: impact on NF-kB signaling and neurotoxicity. Cell Death Dis. 2020;11(6):415. doi:10.1038/s41419-020-2626-6
  • Basu A, Krady JK, Levison SW. Interleukin-1: a master regulator of neuroinflammation. J Neurosci Res. 2004;78(2):151–156. doi:10.1002/jnr.20266
  • Kaushik DK, Thounaojam MC, Kumawat KL, Gupta M, Basu A. Interleukin-1β orchestrates underlying inflammatory responses in microglia via Krüppel-like factor 4. J Neurochem. 2013;127(2):233–244. doi:10.1111/jnc.12382
  • Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162–173. doi:10.1016/S1474-4422(14)70251-0
  • Moisset X, Bouhassira D, Attal N. French guidelines for neuropathic pain: an update and commentary. Rev Neurol (Paris). 2021;177(7):834–837. doi:10.1016/j.neurol.2021.07.004
  • Bouhassira D, Attal N. Translational neuropathic pain research: a clinical perspective. Neuroscience. 2016;338:27–35. doi:10.1016/j.neuroscience.2016.03.029
  • Li CL, Li KC, Wu D, et al. Somatosensory neuron types identified by high-coverage single-cell RNA-sequencing and functional heterogeneity. Cell Res. 2016;26(1):83–102. doi:10.1038/cr.2015.149
  • Kupari J, Usoskin D, Parisien M, et al. Single cell transcriptomics of primate sensory neurons identifies cell types associated with chronic pain. Nat Commun. 2021;12(1):1510. doi:10.1038/s41467-021-21725-z
  • Nguyen MQ, von Buchholtz LJ, Reker AN, Ryba NJ, Davidson S. Single-nucleus transcriptomic analysis of human dorsal root ganglion neurons. eLife. 2021;10. doi:10.7554/eLife.71752
  • Tavares-Ferreira D, Shiers S, Ray PR, et al. Spatial transcriptomics of dorsal root ganglia identifies molecular signatures of human nociceptors. Sci Transl Med. 2022;14(632):eabj8186. doi:10.1126/scitranslmed.abj8186
  • Furman D, Campisi J, Verdin E, et al. Chronic inflammation in the etiology of disease across the life span. Nat Med. 2019;25(12):1822–1832. doi:10.1038/s41591-019-0675-0
  • 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
  • Netea MG, Balkwill F, Chonchol M, et al. A guiding map for inflammation. Nat Immunol. 2017;18(8):826–831. doi:10.1038/ni.3790
  • Kotas ME, Medzhitov R. Homeostasis, inflammation, and disease susceptibility. Cell. 2015;160(5):816–827. doi:10.1016/j.cell.2015.02.010
  • Kato D, Eto K, Nabekura J, Wake H. Activity-dependent functions of non-electrical glial cells. J Biochem. 2018;163(6):457–464. doi:10.1093/jb/mvy023
  • Falk S, Götz M. Glial control of neurogenesis. Curr Opin Neurobiol. 2017;47:188–195. doi:10.1016/j.conb.2017.10.025
  • Ellis A, Bennett DL. Neuroinflammation and the generation of neuropathic pain. Br J Anaesth. 2013;111(1):26–37. doi:10.1093/bja/aet128
  • Calsolaro V, Edison P. Neuroinflammation in Alzheimer’s disease: current evidence and future directions. Alzheimer’s Dementia. 2016;12(6):719–732. doi:10.1016/j.jalz.2016.02.010
  • Walker AK, Kavelaars A, Heijnen CJ, Dantzer R. Neuroinflammation and comorbidity of pain and depression. Pharmacol Rev. 2014;66(1):80–101. doi:10.1124/pr.113.008144
  • Benedetti F, Aggio V, Pratesi ML, Greco G, Furlan R. Neuroinflammation in bipolar depression. Front Psych. 2020;11:71. doi:10.3389/fpsyt.2020.00071
  • Conaghan PG, Cook AD, Hamilton JA, Tak PP. Therapeutic options for targeting inflammatory osteoarthritis pain. Nat Rev Rheumatol. 2019;15(6):355–363. doi:10.1038/s41584-019-0221-y
  • Sánchez-Robles EM, Girón R, Paniagua N, Rodríguez-Rivera C, Pascual D, Goicoechea C. Monoclonal antibodies for chronic pain treatment: present and future. Int J Mol Sci. 2021;22(19):10325. doi:10.3390/ijms221910325
  • Zamri F, de Vries TJ. Use of TNF inhibitors in rheumatoid arthritis and implications for the periodontal status: for the benefit of both? Front Immunol. 2020;11:591365. doi:10.3389/fimmu.2020.591365
  • Piski Z, Gerlinger I, Nepp N, Farkas K, Weber R. TNF-alpha inhibitors and rhinosinusitis-a systematic review and meta-analysis. Am J Rhinol Allergy. 2020;34(3):436–442. doi:10.1177/1945892419898988
  • Minozzi S, Bonovas S, Lytras T, et al. Risk of infections using anti-TNF agents in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: a systematic review and meta-analysis. Expert Opin Drug Saf. 2016;15(sup1):11–34. doi:10.1080/14740338.2016.1240783
  • Nigam GB, Bhandare AP, Antoniou GA, Limdi JK. Systematic review and meta-analysis of dermatological reactions in patients with inflammatory bowel disease treated with anti-tumour necrosis factor therapy. Eur J Gastroenterol Hepatol. 2021;33(3):346–357. doi:10.1097/MEG.0000000000001917
  • Nielsen FH. Dietary magnesium and chronic disease. Adv Chronic Kidney Dis. 2018;25(3):230–235. doi:10.1053/j.ackd.2017.11.005
  • Reginster JY, Strause L, Deroisy R, Lecart MP, Saltman P, Franchimont P. Preliminary report of decreased serum magnesium in postmenopausal osteoporosis. Magnesium. 1989;8(2):106–109.
  • Steidl L, Ditmar R. Blood magnesium, calcium and zinc in osteoporosis. Acta Univ Palacki Olomuc Fac Med. 1991;129:91–98.
  • Serefko A, Szopa A, Poleszak E. Magnesium and depression. Magn res. 2016;29(3):112–119. doi:10.1684/mrh.2016.0407
  • Liu G, Weinger JG, Lu ZL, Xue F, Sadeghpour S. Efficacy and safety of MMFS-01, a synapse density enhancer, for treating cognitive impairment in older adults: a randomized, double-blind, placebo-controlled trial. J Alzheimer’s Dis. 2016;49(4):971–990. doi:10.3233/JAD-150538
  • Morel V, Pickering ME, Goubayon J, Djobo M, Macian N, Pickering G. Magnesium for pain treatment in 2021? state of the art. Nutrients. 2021;13(5):1397. doi:10.3390/nu13051397
  • Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010;65(2):165–177. doi:10.1016/j.neuron.2009.12.026
  • Ying YL, Wei XH, Xu XB, et al. Over-expression of P2X7 receptors in spinal glial cells contributes to the development of chronic postsurgical pain induced by skin/muscle incision and retraction (SMIR) in rats. Exp Neurol. 2014;261:836–843. doi:10.1016/j.expneurol.2014.09.007
  • Chen JL, Zhou X, Liu BL, et al. Normalization of magnesium deficiency attenuated mechanical allodynia, depressive-like behaviors, and memory deficits associated with cyclophosphamide-induced cystitis by inhibiting TNF-alpha/NF-kappaB signaling in female rats. J Neuroinflammation. 2020;17(1):99. doi:10.1186/s12974-020-01786-5
  • Mayer ML, Westbrook GL, Guthrie PB. Voltage-dependent block by Mg2+ of NMDA responses in spinal cord neurones. Nature. 1984;309(5965):261–263. doi:10.1038/309261a0
  • Woolf CJ, Thompson SW. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44(3):293–299. doi:10.1016/0304-3959(91)90100-C
  • Shin HJ, Na HS, Do SH. Magnesium and Pain. Nutrients. 2020;12(8):2184. doi:10.3390/nu12082184
  • Tsien JZ, Huerta PT, Tonegawa S. The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory. Cell. 1996;87(7):1327–1338. doi:10.1016/S0092-8674(00)81827-9
  • Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature. 1999;401(6748):63–69. doi:10.1038/43432
  • Wang D, Jacobs SA, Tsien JZ. Targeting the NMDA receptor subunit NR2B for treating or preventing age-related memory decline. Expert Opin Ther Targets. 2014;18(10):1121–1130. doi:10.1517/14728222.2014.941286
  • Wilson JA, Garry EM, Anderson HA, et al. NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists. Pain. 2005;117(3):421–432. doi:10.1016/j.pain.2005.07.005
  • Qu XX, Cai J, Li MJ, et al. Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain. Exp Neurol. 2009;215(2):298–307. doi:10.1016/j.expneurol.2008.10.018
  • Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer. 2008;44(11):1507–1515. doi:10.1016/j.ejca.2008.04.018
  • Tannock IF, Ahles TA, Ganz PA, Van Dam FS. Cognitive impairment associated with chemotherapy for cancer: report of a workshop. J clin Oncol. 2004;22(11):2233–2239. doi:10.1200/JCO.2004.08.094
  • Ballenger JC, Davidson JR, Lecrubier Y, Nutt DJ, Jones RD, Berard RM. Consensus statement on depression, anxiety, and oncology. J Clin Psychiatry. 2001;62(Suppl 8):64–67.
  • Mazur A, Maier JA, Rock E, Gueux E, Nowacki W, Rayssiguier Y. Magnesium and the inflammatory response: potential physiopathological implications. Arch Biochem Biophys. 2007;458(1):48–56. doi:10.1016/j.abb.2006.03.031
  • Veronese N, Pizzol D, Smith L, Dominguez LJ, Barbagallo M. Effect of magnesium supplementation on inflammatory parameters: a meta-analysis of randomized controlled trials. Nutrients. 2022;14(3):679. doi:10.3390/nu14030679
  • Gile J, Ruan G, Abeykoon J, McMahon MM, Witzig T. Magnesium: the overlooked electrolyte in blood cancers? Blood Rev. 2020;3:100676.
  • McKee JA, Brewer RP, Macy GE, Borel CO, Reynolds JD, Warner DS. Magnesium neuroprotection is limited in humans with acute brain injury. Neurocrit Care. 2005;2(3):342–351. doi:10.1385/NCC:2:3:342
  • Niederberger E, Geisslinger G, Warner D, Warner M. Proteomics in neuropathic pain research. Anesthesiology. 2008;108(2):314–323. doi:10.1097/01.anes.0000299838.13368.6e
  • Sribanditmongkol P, Sheu MJ, Tejwani GA. Inhibition of morphine tolerance and dependence by diazepam and its relation to the CNS Met-enkephalin levels. Brain Res. 1994;645(1–2):1–12. doi:10.1016/0006-8993(94)91631-4
  • Zambotti F, Zonta N, Tammiso R, et al. Effects of diazepam on nociception in rats. Naunyn Schmiedebergs Arch Pharmacol. 1991;344(1):84–89. doi:10.1007/BF00167386
  • Warms CA, Turner JA, Marshall HM, Cardenas DD. Treatments for chronic pain associated with spinal cord injuries: many are tried, few are helpful. ClinJPain. 2002;18(3):154–163.
  • Hu NW, Zhang HM, Hu XD, et al. Protein synthesis inhibition blocks the late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. JNeurophysiol. 2003;89(5):2354–2359. doi:10.1152/jn.01027.2002
  • Woods MJ, Williams DC. Multiple forms and locations for the peripheral-type benzodiazepine receptor. Biochem Pharmacol. 1996;52(12):1805–1814. doi:10.1016/S0006-2952(96)00558-8
  • Cavaliere C, Tramontano L, Fiorenza D, Alfano V, Aiello M, Salvatore M. Gliosis and neurodegenerative diseases: the role of PET and MR Imaging. Front Cell Neurosci. 2020;14:75. doi:10.3389/fncel.2020.00075
  • Rupprecht R, Papadopoulos V, Rammes G, et al. Translocator protein (18 kDa) (TSPO) as a therapeutic target for neurological and psychiatric disorders. Nat Rev Drug Discov. 2010;9(12):971–988. doi:10.1038/nrd3295
  • Wei XH, Wei X, Chen FY, et al. The upregulation of translocator protein (18 kDa) promotes recovery from neuropathic pain in rats. J Neurosci. 2013;33(4):1540–1551. doi:10.1523/JNEUROSCI.0324-12.2013
  • Liu X, Liu H, Xu S, et al. Spinal translocator protein alleviates chronic neuropathic pain behavior and modulates spinal astrocyte-neuronal function in rats with L5 spinal nerve ligation model. Pain. 2016;157(1):103–116. doi:10.1097/j.pain.0000000000000339
  • Hernstadt H, Wang S, Lim G, Mao J. Spinal translocator protein (TSPO) modulates pain behavior in rats with CFA-induced monoarthritis. Brain Res. 2009;1286:42–52. doi:10.1016/j.brainres.2009.06.043
  • Cropper HC, Johnson EM, Haight ES, et al. Longitudinal translocator protein-18 kDa-positron emission tomography imaging of peripheral and central myeloid cells in a mouse model of complex regional pain syndrome. Pain. 2019;160(9):2136–2148. doi:10.1097/j.pain.0000000000001607
  • Setiawan E, Wilson AA, Mizrahi R, et al. Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes. JAMA psych. 2015;72(3):268–275. doi:10.1001/jamapsychiatry.2014.2427
  • Attwells S, Setiawan E, Rusjan PM, et al. A double-blind placebo-controlled trial of minocycline on translocator protein distribution volume in treatment-resistant major depressive disorder. Transl Psychiatry. 2021;11(1):334. doi:10.1038/s41398-021-01450-3
  • Albrecht DS, Ahmed SU, Kettner NW, et al. Neuroinflammation of the spinal cord and nerve roots in chronic radicular pain patients. Pain. 2018;159(5):968–977. doi:10.1097/j.pain.0000000000001171
  • Jung ME, Protective A. Role of translocator protein in Alzheimer’s disease brain. Curr Alzheimer Res. 2020;17(1):3–15. doi:10.2174/1567205017666200217105950
  • Vicente B, Saldivia S, Hormazabal N, Bustos C, Rubí P. Etifoxine is non-inferior than clonazepam for reduction of anxiety symptoms in the treatment of anxiety disorders: a randomized, double blind, non-inferiority trial. Psychopharmacology. 2020;237(11):3357–3367. doi:10.1007/s00213-020-05617-6
  • Xu J, Feng YW, Liu L, et al. Liver X receptor alpha is involved in counteracting mechanical allodynia by inhibiting neuroinflammation in the spinal dorsal horn. Anesthesiology. 2017;127(3):534–547. doi:10.1097/ALN.0000000000001718
  • Flatters SJ. Characterization of a model of persistent postoperative pain evoked by skin/muscle incision and retraction (SMIR). Pain. 2008;135(1–2):119–130. doi:10.1016/j.pain.2007.05.013
  • Zhong X, Wang W, Mao Z, et al. Activation of liver x receptors prevents the spinal LTP induced by skin/muscle retraction in the thigh via SIRT1/NF-Κb pathway. Neurochem Int. 2019;128:106–114. doi:10.1016/j.neuint.2019.04.002
  • Mao Z, Huang R, Xu J, Guo R, Wei X. Liver X receptor α in sciatic nerve exerts an alleviating effect on neuropathic pain behaviors induced by crush injury. Neurochem Res. 2021;46(2):358–366. doi:10.1007/s11064-020-03171-3
  • Li X, Zhong H, Wang Z, et al. Loss of liver X receptor β in astrocytes leads to anxiety-like behaviors via regulating synaptic transmission in the medial prefrontal cortex in mice. Mol Psychiatry. 2021;26:6380–6393. doi:10.1038/s41380-021-01139-5
  • Xu X, Xiao X, Yan Y, Zhang T. Activation of liver X receptors prevents emotional and cognitive dysfunction by suppressing microglial M1-polarization and restoring synaptic plasticity in the hippocampus of mice. Brain Behav Immun. 2021;94:111–124. doi:10.1016/j.bbi.2021.02.026
  • Teodorczyk-Injeyan JA, Triano JJ, McGregor M, Woodhouse L, Injeyan HS. Effect of interactive neurostimulation therapy on inflammatory response in patients with chronic and recurrent mechanical neck pain. J Manipulative Physiol Ther. 2015;38(8):545–554. doi:10.1016/j.jmpt.2015.08.006
  • Teodorczyk-Injeyan JA, McGregor M, Triano JJ, Injeyan SH. Elevated production of nociceptive CC chemokines and sE-selectin in patients with low back pain and the effects of spinal manipulation: a nonrandomized clinical trial. Clin J Pain. 2018;34(1):68–75. doi:10.1097/AJP.0000000000000507
  • Pertin M, Ji RR, Berta T, et al. Upregulation of the voltage-gated sodium channel beta2 subunit in neuropathic pain models: characterization of expression in injured and non-injured primary sensory neurons. J Neurosci. 2005;25(47):10970–10980. doi:10.1523/JNEUROSCI.3066-05.2005
  • Chen C, Bharucha V, Chen Y, et al. Reduced sodium channel density, altered voltage dependence of inactivation, and increased susceptibility to seizures in mice lacking sodium channel beta 2-subunits. Proc Natl Acad Sci U S A. 2002;99(26):17072–17077. doi:10.1073/pnas.212638099
  • Razzaque MS. Magnesium: are we consuming enough? Nutrients. 2018;10(12):1863. doi:10.3390/nu10121863
  • Shibata H, Yoshioka Y, Ikemizu S, et al. Functionalization of tumor necrosis factor-alpha using phage display technique and PEGylation improves its antitumor therapeutic window. Clin Cancer Res. 2004;10(24):8293–8300.
  • Katagiri H, Tanaka K, Manabe T. Requirement of appropriate glutamate concentrations in the synaptic cleft for hippocampal LTP induction. Eur J Neurosci. 2001;14(3):547–553. doi:10.1046/j.0953-816x.2001.01664.x
  • Wang ZY, Zhang YQ, Zhao ZQ. Inhibition of tetanically sciatic stimulation-induced LTP of spinal neurons and Fos expression by disrupting glutamate transporter GLT-1. Neuropharmacology. 2006;51(4):764–772. doi:10.1016/j.neuropharm.2006.05.024
  • Murphy N, Cowley TR, Richardson JC, et al. The neuroprotective effect of a specific P2X7 receptor antagonist derives from its ability to inhibit assembly of the NLRP3 inflammasome in glial cells. Brain Pathol. 2012;22(3):295–306. doi:10.1111/j.1750-3639.2011.00531.x