Abstract
Spinal cord injury (SCI) causes maladaptive changes to nociceptive synaptic circuits within the injured spinal cord. Changes also occur at remote regions including the brain stem, limbic system, cortex, and dorsal root ganglia. These maladaptive nociceptive synaptic circuits frequently cause neuronal hyperexcitability in the entire nervous system and enhance nociceptive transmission, resulting in chronic central neuropathic pain following SCI. The underlying mechanism of chronic neuropathic pain depends on the neuroanatomical structures and electrochemical communication between pre- and postsynaptic neuronal membranes, and propagation of synaptic transmission in the ascending pain pathways. In the nervous system, neurons are the only cell type that transmits nociceptive signals from peripheral receptors to supraspinal systems due to their neuroanatomical and electrophysiological properties. However, the entire range of nociceptive signaling is not mediated by any single neuron. Current literature describes regional studies of electrophysiological or neurochemical mechanisms for enhanced nociceptive transmission post-SCI, but few studies report the electrophysiological, neurochemical, and neuroanatomical changes across the entire nervous system following a regional SCI. We, along with others, have continuously described the enhanced nociceptive transmission in the spinal dorsal horn, brain stem, thalamus, and cortex in SCI-induced chronic central neuropathic pain condition, respectively. Thus, this review summarizes the current understanding of SCI-induced neuronal hyperexcitability and maladaptive nociceptive transmission in the entire nervous system that contributes to chronic central neuropathic pain.
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References
Ackery AD, Norenberg MD, Krassioukov A (2007) Calcitonin gene-related peptide immunoreactivity in chronic human spinal cord injury. Spinal Cord 45(10):678–686. https://doi.org/10.1038/sj.sc.3102020
Aguilar J, Humanes-Valera D, Alonso-Calvino E, Yague JG, Moxon KA, Oliviero A, Foffani G (2010) Spinal cord injury immediately changes the state of the brain. J Neurosci 30(22):7528–7537. https://doi.org/10.1523/Jneurosci.0379-10.2010
Aguilar J, Pulecchi F, Dilena R, Oliviero A, Priori A, Foffani G (2011) Spinal direct current stimulation modulates the activity of gracile nucleus and primary somatosensory cortex in anaesthetized rats. J Physiol 589(20):4981–4996. https://doi.org/10.1113/jphysiol.2011.214189
Alto LT, Havton LA, Conner JM, Hollis ER 2nd, Blesch A, Tuszynski MH (2009) Chemotropic guidance facilitates axonal regeneration and synapse formation after spinal cord injury. Nat Neurosci 12(9):1106–1113. https://doi.org/10.1038/nn.2365
Apkarian AV, Bushnell MC, Treede RD, Zubieta JK (2005) Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 9(4):463–484. https://doi.org/10.1016/j.ejpain.2004.11.001
Baastrup C, Jensen TS, Finnerup NB (2018) Coexisting mechanical hypersensitivity and anxiety in a rat model of spinal cord injury and the effect of pregabalin, morphine, and midazolam treatment. Scand J Pain 2(3):139–145. https://doi.org/10.1016/j.sjpain.2011.02.001
Bavencoffe A, Li Y, Wu Z, Yang Q, Herrera J, Kennedy EJ, Walters ET, Dessauer CW (2016) Persistent electrical activity in primary nociceptors after spinal cord injury is maintained by scaffolded adenylyl cyclase and protein kinase A and is associated with altered adenylyl cyclase regulation. J Neurosci 36(5):1660–1668. https://doi.org/10.1523/JNEUROSCI.0895-15.2016
Bedi SS, Yang Q, Crook RJ, Du J, Wu Z, Fishman HM, Grill RJ, Carlton SM, Walters ET (2010) Chronic spontaneous activity generated in the somata of primary nociceptors is associated with pain-related behavior after spinal cord injury. J Neurosci 30(44):14870–14882. https://doi.org/10.1523/JNEUROSCI.2428-10.2010
Bedi SS, Lago MT, Masha LI, Crook RJ, Grill RJ, Walters ET (2012) Spinal cord injury triggers an intrinsic growth-promoting state in nociceptors. J Neurotrauma 29(5):925–935. https://doi.org/10.1089/neu.2011.2007
Bernstein JJ, Ganchrow D (1981) Relationship of afferentation with soma size of nucleus gracilis neurons after bilateral dorsal column lesion in the rat. Exp Neurol 71(3):452–463
Boadas-Vaello P, Homs J, Reina F, Carrera A, Verdu E (2017) Neuroplasticity of supraspinal structures associated with pathological pain. Anat Rec 300(8):1481–1501. https://doi.org/10.1002/ar.23587
Brown A, Ricci MJ, Weaver LC (2007) NGF mRNA is expressed in the dorsal root ganglia after spinal cord injury in the rat. Exp Neurol 205(1):283–286. https://doi.org/10.1016/j.expneurol.2007.01.025
Bruce JC, Oatway MA, Weaver LC (2002) Chronic pain after clip-compression injury of the rat spinal cord. Exp Neurol 178(1):33–48
Burke D, Fullen BM, Stokes D, Lennon O (2017) Neuropathic pain prevalence following spinal cord injury: a systematic review and meta-analysis. Eur J Pain 21(1):29–44. https://doi.org/10.1002/ejp.905
Cao XC, Pappalardo LW, Waxman SG, Tan AM (2017) Dendritic spine dysgenesis in superficial dorsal horn sensory neurons after spinal cord injury. Mol Pain 13:1744806916688016. https://doi.org/10.1177/1744806916688016
Carlton SM, Du J, Tan HY, Nesic O, Hargett GL, Bopp AC, Yamani A, Lin Q, Willis WD, Hulsebosch CE (2009) Peripheral and central sensitization in remote spinal cord regions contribute to central neuropathic pain after spinal cord injury. Pain 147(1–3):265–276. https://doi.org/10.1016/j.pain.2009.09.030
Carter MW, Johnson KM, Lee JY, Hulsebosch CE, Gwak YS (2016) Comparison of mechanical allodynia and recovery of locomotion and bladder function by different parameters of low thoracic spinal contusion injury in rats. Korean J Pain 29(2):86–95. https://doi.org/10.3344/kjp.2016.29.2.86
Chang E, Chen X, Kim M, Gong N, Bhatia S, Luo ZD (2015) Differential effects of voltage-gated calcium channel blockers on calcium channel alpha-2-delta-1 subunit protein-mediated nociception. Eur J Pain 19(5):639–648. https://doi.org/10.1002/ejp.585
Chen Y, Oatway MA, Weaver LC (2009) Blockade of the 5-HT3 receptor for days causes sustained relief from mechanical allodynia following spinal cord injury. J Neurosci Res 87(2):418–424. https://doi.org/10.1002/jnr.21860
Christensen MD, Hulsebosch CE (1997) Spinal cord injury and anti-NGF treatment results in changes in CGRP density and distribution in the dorsal horn in the rat. Exp Neurol 147(2):463–475. https://doi.org/10.1006/exnr.1997.6608
Chung JM, Surmeier DJ, Lee KH, Sorkin LS, Honda CN, Tsong Y, Willis WD (1986) Classification of primate spinothalamic and somatosensory thalamic neurons based on cluster analysis. J Neurophysiol 56(2):308–327. https://doi.org/10.1152/jn.1986.56.2.308
Condes-Lara M, Martinez-Lorenzana G, Rojas-Piloni G, Tello-Garcia IA, Manzano-Garcia A, Rubio-Beltran E, Gonzalez-Hernandez A (2018) Axons of individual dorsal horn neurons bifurcated to project in both the anterolateral and the postsynaptic dorsal column systems. Neuroscience 371:178–190. https://doi.org/10.1016/j.neuroscience.2017.11.050
Crown ED, Ye Z, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE (2006) Increases in the activated forms of ERK 1/2, p38 MAPK, and CREB are correlated with the expression of at-level mechanical allodynia following spinal cord injury. Exp Neurol 199(2):397–407. https://doi.org/10.1016/j.expneurol.2006.01.003
Crown ED, Gwak YS, Ye Z, Johnson KM, Hulsebosch CE (2008) Activation of p38 MAP kinase is involved in central neuropathic pain following spinal cord injury. Exp Neurol 213(2):257–267. https://doi.org/10.1016/j.expneurol.2008.05.025
Crown ED, Gwak YS, Ye Z, Yu Tan H, Johnson KM, Xu GY, McAdoo DJ, Hulsebosch CE (2012) Calcium/calmodulin dependent kinase II contributes to persistent central neuropathic pain following spinal cord injury. Pain 153(3):710–721. https://doi.org/10.1016/j.pain.2011.12.013
Cui Y, Xu J, Dai R, He L (2012) The interface between inhibition of descending noradrenergic pain control pathways and negative affects in post-traumatic pain patients. Upsala J Med Sci 117(3):293–299. https://doi.org/10.3109/03009734.2011.653606
Daou I, Tuttle AH, Longo G, Wieskopf JS, Bonin RP, Ase AR, Wood JN, De Koninck Y, Ribeiro-da-Silva A, Mogil JS, Seguela P (2013) Remote optogenetic activation and sensitization of pain pathways in freely moving mice. J Neurosci 33(47):18631–18640. https://doi.org/10.1523/JNEUROSCI.2424-13.2013
Daou I, Beaudry H, Ase AR, Wieskopf JS, Ribeiro-da-Silva A, Mogil JS, Seguela P (2016) Optogenetic silencing of Nav1.8-positive afferents alleviates inflammatory and neuropathic pain. eNeuro https://doi.org/10.1523/ENEURO.0140-15.2016
David-Pereira A, Sagalajev B, Wei H, Almeida A, Pertovaara A, Pinto-Ribeiro F (2017) The medullary dorsal reticular nucleus as a relay for descending pronociception induced by the mGluR5 in the rat infralimbic cortex. Neuroscience 349:341–354. https://doi.org/10.1016/j.neuroscience.2017.02.046
Dawes JM, Weir GA, Middleton SJ, Patel R, Chisholm KI, Pettingill P, Peck LJ, Sheridan J, Shakir A, Jacobson L, Gutierrez-Mecinas M, Galino J, Walcher J, Kuhnemund J, Kuehn H, Sanna MD, Lang B, Clark AJ, Themistocleous AC, Iwagaki N, West SJ, Werynska K, Carroll L, Trendafilova T, Menassa DA, Giannoccaro MP, Coutinho E, Cervellini I, Tewari D, Buckley C, Leite MI, Wildner H, Zeilhofer HU, Peles E, Todd AJ, McMahon SB, Dickenson AH, Lewin GR, Vincent A, Bennett DL (2018) Immune or genetic-mediated disruption of CASPR2 causes pain hypersensitivity due to enhanced primary afferent excitability. Neuron 97(4):806–822. https://doi.org/10.1016/j.neuron.2018.01.033
Defrin R, Ohry A, Blumen N, Urca G (2001) Characterization of chronic pain and somatosensory function in spinal cord injury subjects. Pain 89(2–3):253–263
Detloff MR, Wade RE Jr, Houle JD (2013) Chronic at- and below-level pain after moderate unilateral cervical spinal cord contusion in rats. J Neurotrauma 30(10):884–890. https://doi.org/10.1089/neu.2012.2632
Devaux S, Cizkova D, Mallah K, Karnoub MA, Laouby Z, Kobeissy F, Blasko J, Nataf S, Pays L, Meriaux C, Fournier I, Salzet M (2017) RhoA inhibitor treatment at acute phase of spinal cord injury may induce neurite outgrowth and synaptogenesis. Mol Cell Proteomics 16(8):1394–1415. https://doi.org/10.1074/mcp.M116.064881
Devor M (2009) Ectopic discharge in Abeta afferents as a source of neuropathic pain. Exp Brain Res 196(1):115–128. https://doi.org/10.1007/s00221-009-1724-6
Drew GM, Siddall PJ, Duggan AW (2001) Responses of spinal neurones to cutaneous and dorsal root stimuli in rats with mechanical allodynia after contusive spinal cord injury. Brain Res 893(1–2):59–69
Dunlop SA (2008) Activity-dependent plasticity: implications for recovery after spinal cord injury. Trends Neurosci 31(8):410–418. https://doi.org/10.1016/j.tins.2008.05.004
Eaton MJ, Plunkett JA, Karmally S, Martinez MA, Montanez K (1998) Changes in GAD- and GABA- immunoreactivity in the spinal dorsal horn after peripheral nerve injury and promotion of recovery by lumbar transplant of immortalized serotonergic precursors. J Chem Neuroanat 16(1):57–72
Felix ER, Widerstrom-Noga EG (2009) Reliability and validity of quantitative sensory testing in persons with spinal cord injury and neuropathic pain. J Rehabil Res Dev 46(1):69–83
Ferrington DG, Sorkin LS, Willis WD Jr (1986) Responses of spinothalamic tract cells in the cat cervical spinal cord to innocuous and graded noxious stimuli. Somatosens Res 3(4):339–358
Finnerup NB, Johannesen IL, Fuglsang-Frederiksen A, Bach FW, Jensen TS (2003) Sensory function in spinal cord injury patients with and without central pain. Brain 126(Pt 1):57–70
Finnerup NB, Sorensen L, Biering-Sorensen F, Johannesen IL, Jensen TS (2007) Segmental hypersensitivity and spinothalamic function in spinal cord injury pain. Exp Neurol 207(1):139–149. https://doi.org/10.1016/j.expneurol.2007.06.001
Finnerup NB, Norrbrink C, Trok K, Piehl F, Johannesen IL, Sorensen JC, Jensen TS, Werhagen L (2014) Phenotypes and predictors of pain following traumatic spinal cord injury: a prospective study. J Pain 15(1):40–48. https://doi.org/10.1016/j.jpain.2013.09.008
Finnerup NB, Jensen MP, Norrbrink C, Trok K, Johannesen IL, Jensen TS, Werhagen L (2016) A prospective study of pain and psychological functioning following traumatic spinal cord injury. Spinal Cord 54(10):816–821. https://doi.org/10.1038/sc.2015.236
Francois A, Low SA, Sypek EI, Christensen AJ, Sotoudeh C, Beier KT, Ramakrishnan C, Ritola KD, Sharif-Naeini R, Deisseroth K, Delp SL, Malenka RC, Luo L, Hantman AW, Scherrer G (2017) A brainstem-spinal cord inhibitory circuit for mechanical pain modulation by GABA and enkephalins. Neuron 93(4):822–839. https://doi.org/10.1016/j.neuron.2017.01.008
Fu X, Shen Y, Wang W, Li X (2018) MiR-30a-5p ameliorates spinal cord injury-induced inflammatory responses and oxidative stress by targeting Neurod 1 through MAPK/ERK signalling. Clin Exp Pharmacol Physiol 45(1):68–74. https://doi.org/10.1111/1440-1681.12856
Galan-Arriero I, Avila-Martin G, Ferrer-Donato A, Gomez-Soriano J, Bravo-Esteban E, Taylor J (2014) Oral administration of the p38alpha MAPK inhibitor, UR13870, inhibits affective pain behavior after spinal cord injury. Pain 155(10):2188–2198. https://doi.org/10.1016/j.pain.2014.08.030
Gangadharan V, Wang X, Luo C (2017) Cyclic GMP-dependent protein kinase-I localized in nociceptors modulates nociceptive cortical neuronal activity and pain hypersensitivity. Mol Pain 13:1744806917701743. https://doi.org/10.1177/1744806917701743
Grau JW, Huang YJ (2018) Metaplasticity within the spinal cord: Evidence brain-derived neurotrophic factor (BDNF), tumor necrosis factor (TNF), and alterations in GABA function (ionic plasticity) modulate pain and the capacity to learn. Neurobiol Learn Mem 154:121–135. https://doi.org/10.1016/j.nlm.2018.04.007
Gruener H, Zeilig G, Laufer Y, Blumen N, Defrin R (2016) Differential pain modulation properties in central neuropathic pain after spinal cord injury. Pain 157(7):1415–1424. https://doi.org/10.1097/j.pain.0000000000000532
Guptarak J, Wanchoo S, Durham-Lee J, Wu Y, Zivadinovic D, Paulucci-Holthauzen A, Nesic O (2013) Inhibition of IL-6 signaling: a novel therapeutic approach to treating spinal cord injury pain. Pain 154(7):1115–1128. https://doi.org/10.1016/j.pain.2013.03.026
Gustin SM, Wrigley PJ, Siddall PJ, Henderson LA (2010) Brain anatomy changes associated with persistent neuropathic pain following spinal cord injury. Cereb Cortex 20(6):1409–1419. https://doi.org/10.1093/cercor/bhp205
Gwak YS, Hulsebosch CE (2011) Neuronal hyperexcitability: a substrate for central neuropathic pain after spinal cord injury. Curr Pain Headache Rep 15(3):215–222. https://doi.org/10.1007/s11916-011-0186-2
Gwak YS, Nam TS, Paik KS, Hulsebosch CE, Leem JW (2003) Attenuation of mechanical hyperalgesia following spinal cord injury by administration of antibodies to nerve growth factor in the rat. Neurosci Lett 336(2):117–120
Gwak YS, Tan HY, Nam TS, Paik KS, Hulsebosch CE, Leem JW (2006) Activation of spinal GABA receptors attenuates chronic central neuropathic pain after spinal cord injury. J Neurotrauma 23(7):1111–1124. https://doi.org/10.1089/neu.2006.23.1111
Gwak YS, Kim HK, Kim HY, Leem JW (2010) Bilateral hyperexcitability of thalamic VPL neurons following unilateral spinal injury in rats. J Physiol Sci 60(1):59–66. https://doi.org/10.1007/s12576-009-0066-2
Gwak YS, Kang J, Unabia GC, Hulsebosch CE (2012) Spatial and temporal activation of spinal glial cells: role of gliopathy in central neuropathic pain following spinal cord injury in rats. Exp Neurol 234(2):362–372. https://doi.org/10.1016/j.expneurol.2011.10.010
Gwak YS, Hassler SE, Hulsebosch CE (2013) Reactive oxygen species contribute to neuropathic pain and locomotor dysfunction via activation of CamKII in remote segments following spinal cord contusion injury in rats. Pain 154(9):1699–1708. https://doi.org/10.1016/j.pain.2013.05.018
Gwak YS, Kim HY, Lee BH, Yang CH (2016) Combined approaches for the relief of spinal cord injury-induced neuropathic pain. Complement Ther Med 25:27–33. https://doi.org/10.1016/j.ctim.2015.12.021
Gwak YS, Hulsebosch CE, Leem JW (2017) Neuronal-glial interactions maintain chronic neuropathic pain after spinal cord injury. Neural Plast 2017:2480689. https://doi.org/10.1155/2017/2480689
Hains BC, Johnson KM, McAdoo DJ, Eaton MJ, Hulsebosch CE (2001) Engraftment of serotonergic precursors enhances locomotor function and attenuates chronic central pain behavior following spinal hemisection injury in the rat. Exp Neurol 171(2):361–378. https://doi.org/10.1006/exnr.2001.7751
Hains BC, Willis WD, Hulsebosch CE (2002) Differential electrophysiological effects of brain-derived neurotrophic factor on dorsal horn neurons following chronic spinal cord hemisection injury in the rat. Neurosci Lett 320(3):125–128
Hains BC, Johnson KM, Eaton MJ, Willis WD, Hulsebosch CE (2003a) Serotonergic neural precursor cell grafts attenuate bilateral hyperexcitability of dorsal horn neurons after spinal hemisection in rat. Neuroscience 116(4):1097–1110
Hains BC, Klein JP, Saab CY, Craner MJ, Black JA, Waxman SG (2003b) Upregulation of sodium channel Nav1.3 and functional involvement in neuronal hyperexcitability associated with central neuropathic pain after spinal cord injury. J Neurosci 23(26):8881–8892
Hains BC, Saab CY, Waxman SG (2006) Alterations in burst firing of thalamic VPL neurons and reversal by Na(v)1.3 antisense after spinal cord injury. J Neurophysiol 95(6):3343–3352. https://doi.org/10.1152/jn.01009.2005
Hama A, Sagen J (2011) Antinociceptive effect of riluzole in rats with neuropathic spinal cord injury pain. J Neurotrauma 28(1):127–134. https://doi.org/10.1089/neu.2010.1539
Hao JX, Xu XJ, Yu YX, Seiger A, Wiesenfeld-Hallin Z (1991) Hypersensitivity of dorsal horn wide dynamic range neurons to cutaneous mechanical stimuli after transient spinal cord ischemia in the rat. Neurosci Lett 128(1):105–108
Hao JX, Kupers RC, Xu XJ (2004) Response characteristics of spinal cord dorsal horn neurons in chronic allodynic rats after spinal cord injury. J Neurophysiol 92(3):1391–1399. https://doi.org/10.1152/jn.00121.2004
Hasbargen T, Ahmed MM, Miranpuri G, Li L, Kahle KT, Resnick D, Sun D (2010) Role of NKCC1 and KCC2 in the development of chronic neuropathic pain following spinal cord injury. Ann N Y Acad Sci 1198:168–172. https://doi.org/10.1111/j.1749-6632.2010.05462.x
Hatch MN, Cushing TR, Carlson GD, Chang EY (2018) Neuropathic pain and SCI: identification and treatment strategies in the 21st century. J Neurol Sci 384:75–83. https://doi.org/10.1016/j.jns.2017.11.018
Horiuchi H, Ogata T, Morino T, Takeba J, Yamamoto H (2003) Serotonergic signaling inhibits hyperalgesia induced by spinal cord damage. Brain Res 963(1–2):312–320
Hoschouer EL, Yin FQ, Jakeman LB (2009) L1 cell adhesion molecule is essential for the maintenance of hyperalgesia after spinal cord injury. Exp Neurol 216(1):22–34. https://doi.org/10.1016/j.expneurol.2008.10.025
Hou S, Duale H, Rabchevsky AG (2009) Intraspinal sprouting of unmyelinated pelvic afferents after complete spinal cord injury is correlated with autonomic dysreflexia induced by visceral pain. Neuroscience 159(1):369–379. https://doi.org/10.1016/j.neuroscience.2008.12.022
Huang YJ, Lee KH, Murphy L, Garraway SM, Grau JW (2016) Acute spinal cord injury (SCI) transforms how GABA affects nociceptive sensitization. Exp Neurol 285(Pt A):82–95. https://doi.org/10.1016/j.expneurol.2016.09.005
Hubscher CH, Johnson RD (1999) Changes in neuronal receptive field characteristics in caudal brain stem following chronic spinal cord injury. J Neurotrauma 16(6):533–541. https://doi.org/10.1089/neu.1999.16.533
Hubscher CH, Johnson RD (2006) Chronic spinal cord injury induced changes in the responses of thalamic neurons. Exp Neurol 197(1):177–188. https://doi.org/10.1016/j.expneurol.2005.09.007
Hughes AS, Averill S, King VR, Molander C, Shortland PJ (2008) Neurochemical characterization of neuronal populations expressing protein kinase C gamma isoform in the spinal cord and gracile nucleus of the rat. Neuroscience 153(2):507–517. https://doi.org/10.1016/j.neuroscience.2008.01.082
Jain N, Florence SL, Qi HX, Kaas JH (2000) Growth of new brainstem connections in adult monkeys with massive sensory loss. Proc Natl Acad Sci USA 97(10):5546–5550. https://doi.org/10.1073/pnas.090572597
Jang JY, Lee SH, Kim M, Ryu JS (2014) Characteristics of neuropathic pain in patients with spinal cord injury. Ann Rehabil Med 38(3):327–334. https://doi.org/10.5535/arm.2014.38.3.327
Jiang L, Voulalas P, Ji Y, Masri R (2016) Post-translational modification of cortical GluA receptors in rodents following spinal cord lesion. Neuroscience 316:122–129. https://doi.org/10.1016/j.neuroscience.2015.12.038
Joukal M, Klusakova I, Dubovy P (2016) Direct communication of the spinal subarachnoid space with the rat dorsal root ganglia. Ann Anat 205:9–15. https://doi.org/10.1016/j.aanat.2016.01.004
Jutzeler CR, Huber E, Callaghan MF, Luechinger R, Curt A, Kramer JL, Freund P (2016) Association of pain and CNS structural changes after spinal cord injury. Sci Rep 6:18534. https://doi.org/10.1038/srep18534
Kalous A, Osborne PB, Keast JR (2009) Spinal cord compression injury in adult rats initiates changes in dorsal horn remodeling that may correlate with development of neuropathic pain. J Comp Neurol 513(6):668–684. https://doi.org/10.1002/cne.21986
Kambi N, Halder P, Rajan R, Arora V, Chand P, Arora M, Jain N (2014) Large-scale reorganization of the somatosensory cortex following spinal cord injuries is due to brainstem plasticity. Nat Commun 5:3602. https://doi.org/10.1038/ncomms4602
Kato H, Kanellopoulos GK, Matsuo S, Wu YJ, Jacquin MF, Hsu CY, Kouchoukos NT, Choi DW (1997) Neuronal apoptosis and necrosis following spinal cord ischemia in the rat. Exp Neurol 148(2):464–474. https://doi.org/10.1006/exnr.1997.6707
Kato K, Koda M, Takahashi H, Sakuma T, Inada T, Kamiya K, Ota M, Maki S, Okawa A, Takahashi K, Yamazaki M, Aramomi M, Hashimoto M, Ikeda O, Mannoji C, Furuya T (2015) Granulocyte colony-stimulating factor attenuates spinal cord injury-induced mechanical allodynia in adult rats. J Neurol Sci 355(1–2):79–83. https://doi.org/10.1016/j.jns.2015.05.024
Keller AV, Hainline C, Rees K, Krupp S, Prince D, Wood BD, Shum-Siu A, Burke DA, Petruska JC, Magnuson DSK (2019) Nociceptor-dependent locomotor dysfunction after clinically-modeled hindlimb muscle stretching in adult rats with spinal cord injury. Exp Neurol. https://doi.org/10.1016/j.expneurol.2019.03.006
Kim J, Back SK, Yoon YW, Hong SK, Na HS (2005) Dorsal column lesion reduces mechanical allodynia in the induction, but not the maintenance, phase in spinal hemisected rats. Neurosci Lett 379(3):218–222. https://doi.org/10.1016/j.neulet.2004.12.074
Kim HY, Wang J, Gwak YS (2012) Gracile neurons contribute to the maintenance of neuropathic pain in peripheral and central neuropathic models. J Neurotrauma 29(16):2587–2592. https://doi.org/10.1089/neu.2012.2396
Kitayama T (2018) The role of K(+)-Cl(-)-cotransporter-2 in neuropathic pain. Neurochem Res 43(1):101–106. https://doi.org/10.1007/s11064-017-2344-3
Knerlich-Lukoschus F, Noack M, von der Ropp-Brenner B, Lucius R, Mehdorn HM, Held-Feindt J (2011) Spinal cord injuries induce changes in CB1 cannabinoid receptor and C-C chemokine expression in brain areas underlying circuitry of chronic pain conditions. J Neurotrauma 28(4):619–634. https://doi.org/10.1089/neu.2010.1652
Ko MY, Jang EY, Lee JY, Kim SP, Whang SH, Lee BH, Kim HY, Yang CH, Cho HJ, Gwak YS (2018) The role of ventral tegmental area gamma-aminobutyric acid in chronic neuropathic pain after spinal cord injury in rats. J Neurotrauma 35(15):1755–1764. https://doi.org/10.1089/neu.2017.5381
Kopach O, Medvediev V, Krotov V, Borisyuk A, Tsymbaliuk V, Voitenko N (2017) Opposite, bidirectional shifts in excitation and inhibition in specific types of dorsal horn interneurons are associated with spasticity and pain post-SCI. Sci Rep 7(1):5884. https://doi.org/10.1038/s41598-017-06049-7
Kumar S, Jain T, Velpandian Y, Petrovich Gerasimenko Y, Avelev V, Behari J, Behari M, Mathur R (2013) Exposure to extremely low-frequency magnetic field restores spinal cord injury-induced tonic pain and its related neurotransmitter concentration in the brain. Electromagn Biol Med 32(4):471–483. https://doi.org/10.3109/15368378.2012.743907
Kumru H, Soler D, Vidal J, Tormos JM, Pascual-Leone A, Valls-Sole J (2012) Evoked potentials and quantitative thermal testing in spinal cord injury patients with chronic neuropathic pain. Clin Neurophysiol 123(3):598–604. https://doi.org/10.1016/j.clinph.2011.07.038
Lampert A, Hains BC, Waxman SG (2006) Upregulation of persistent and ramp sodium current in dorsal horn neurons after spinal cord injury. Exp Brain Res 174(4):660–666. https://doi.org/10.1007/s00221-006-0511-x
Landmann G, Berger MF, Stockinger L, Opsommer E (2017) Usefulness of laser-evoked potentials and quantitative sensory testing in the diagnosis of neuropathic spinal cord injury pain: a multiple case study. Spinal Cord 55(6):575–582. https://doi.org/10.1038/sc.2016.191
Lee JY, Kam YL, Oh J, Kim DH, Choi JS, Choi HY, Han S, Youn I, Choo HP, Yune TY (2017) HYP-17, a novel voltage-gated sodium channel blocker, relieves inflammatory and neuropathic pain in rats. Pharmacol Biochem Behav 153:116–129. https://doi.org/10.1016/j.pbb.2016.12.013
Lee-Kubli CA, Ingves M, Henry KW, Shiao R, Collyer E, Tuszynski MH, Campana WM (2016) Analysis of the behavioral, cellular and molecular characteristics of pain in severe rodent spinal cord injury. Exp Neurol 278:91–104. https://doi.org/10.1016/j.expneurol.2016.01.009
Leem JW, Lee BH, Willis WD, Chung JM (1994) Grouping of somatosensory neurons in the spinal cord and the gracile nucleus of the rat by cluster analysis. J Neurophysiol 72(6):2590–2597. https://doi.org/10.1152/jn.1994.72.6.2590
Leem JW, Kim HK, Hulsebosch CE, Gwak YS (2010) Ionotropic glutamate receptors contribute to maintained neuronal hyperexcitability following spinal cord injury in rats. Exp Neurol 224(1):321–324. https://doi.org/10.1016/j.expneurol.2010.02.012
Lewinter RD, Skinner K, Julius D, Basbaum AI (2004) Immunoreactive TRPV-2 (VRL-1), a capsaicin receptor homolog, in the spinal cord of the rat. J Comp Neurol 470(4):400–408. https://doi.org/10.1002/cne.20024
Li XM, Meng J, Li LT, Guo T, Yang LK, Shi QX, Li XB, Chen Y, Yang Q, Zhao JN (2017) Effect of ZBD-2 on chronic pain, depressive-like behaviors, and recovery of motor function following spinal cord injury in mice. Behav Brain Res 322(Pt A):92–99. https://doi.org/10.1016/j.bbr.2017.01.025
Liao CC, Reed JL, Qi HX, Sawyer EK, Kaas JH (2018) Second-order spinal cord pathway contributes to cortical responses after long recoveries from dorsal column injury in squirrel monkeys. Proc Natl Acad Sci USA 115(16):4258–4263. https://doi.org/10.1073/pnas.1718826115
Liu J, Wolfe D, Hao S, Huang S, Glorioso JC, Mata M, Fink DJ (2004) Peripherally delivered glutamic acid decarboxylase gene therapy for spinal cord injury pain. Mol Ther 10(1):57–66. https://doi.org/10.1016/j.ymthe.2004.04.017
Loubser PG, Donovan WH (1991) Diagnostic spinal anaesthesia in chronic spinal cord injury pain. Paraplegia 29(1):25–36. https://doi.org/10.1038/sc.1991.4
Luo Y, Fu C, Wang Z, Zhang Z, Wang H, Liu Y (2015) Asiaticoside attenuates the effects of spinal cord injury through antioxidant and antiinflammatory effects, and inhibition of the p38MAPK mechanism. Mol Med Rep 12(6):8294–8300. https://doi.org/10.3892/mmr.2015.4425
Maldonado-Bouchard S, Peters K, Woller SA, Madahian B, Faghihi U, Patel S, Bake S, Hook MA (2016) Inflammation is increased with anxiety- and depression-like signs in a rat model of spinal cord injury. Brain Behav Immun 51:176–195. https://doi.org/10.1016/j.bbi.2015.08.009
Massey JM, Amps J, Viapiano MS, Matthews RT, Wagoner MR, Whitaker CM, Alilain W, Yonkof AL, Khalyfa A, Cooper NG, Silver J, Onifer SM (2008) Increased chondroitin sulfate proteoglycan expression in denervated brainstem targets following spinal cord injury creates a barrier to axonal regeneration overcome by chondroitinase ABC and neurotrophin-3. Exp Neurol 209(2):426–445. https://doi.org/10.1016/j.expneurol.2007.03.029
Matsubayashi K, Nagoshi N, Komaki Y, Kojima K, Shinozaki M, Tsuji O, Iwanami A, Ishihara R, Takata N, Matsumoto M, Mimura M, Okano H, Nakamura M (2018) Assessing cortical plasticity after spinal cord injury by using resting-state functional magnetic resonance imaging in awake adult mice. Sci Rep 8(1):14406. https://doi.org/10.1038/s41598-018-32766-8
McAdoo DJ, Wu P (2008) Microdialysis in central nervous system disorders and their treatment. Pharmacol Biochem Behav 90(2):282–296. https://doi.org/10.1016/j.pbb.2008.03.001
Meisner JG, Marsh AD, Marsh DR (2010) Loss of GABAergic interneurons in laminae I-III of the spinal cord dorsal horn contributes to reduced GABAergic tone and neuropathic pain after spinal cord injury. J Neurotrauma 27(4):729–737. https://doi.org/10.1089/neu.2009.1166
Miladinovic K (2009) Spinal cord injury and chronic pain. Med Arh 63(2):106–107
Mills CD, Fullwood SD, Hulsebosch CE (2001) Changes in metabotropic glutamate receptor expression following spinal cord injury. Exp Neurol 170(2):244–257. https://doi.org/10.1006/exnr.2001.7721
Molander C, Grant G (1986) Laminar distribution and somatotopic organization of primary afferent fibers from hindlimb nerves in the dorsal horn. A study by transganglionic transport of horseradish peroxidase in the rat. Neuroscience 19(1):297–312
Mole TB, MacIver K, Sluming V, Ridgway GR, Nurmikko TJ (2014) Specific brain morphometric changes in spinal cord injury with and without neuropathic pain. Neuroimage Clin 5:28–35. https://doi.org/10.1016/j.nicl.2014.05.014
Moshourab RA, Schafer M, Al-Chaer ED (2015) Chronic pain in neurotrauma: implications on spinal cord and traumatic brain injury. In: Kobeissy FH (ed) Brain neurotrauma: Molecular, neuropsychological, and rehabilitation aspects. Frontiers in neuroengineering. CRC Press, Boca Raton.
Mothe AJ, Tassew NG, Shabanzadeh AP, Penheiro R, Vigouroux RJ, Huang L, Grinnell C, Cui YF, Fung E, Monnier PP, Mueller BK, Tator CH (2017) RGMa inhibition with human monoclonal antibodies promotes regeneration, plasticity and repair, and attenuates neuropathic pain after spinal cord injury. Sci Rep 7(1):10529. https://doi.org/10.1038/s41598-017-10987-7
Muqeem T, Ghosh B, Pinto V, Lepore AC, Covarrubias M (2018) Regulation of nociceptive glutamatergic signaling by presynaptic Kv3.4 channels in the rat spinal dorsal horn. J Neurosci 38(15):3729–3740. https://doi.org/10.1523/JNEUROSCI.3212-17.2018
Nardone R, Holler Y, Sebastianelli L, Versace V, Saltuari L, Brigo F, Lochner P, Trinka E (2018) Cortical morphometric changes after spinal cord injury. Brain Res Bull 137:107–119. https://doi.org/10.1016/j.brainresbull.2017.11.013
Nasirinezhad F, Hosseini M, Karami Z, Yousefifard M, Janzadeh A (2016) Spinal 5-HT3 receptor mediates nociceptive effect on central neuropathic pain; possible therapeutic role for tropisetron. J Spinal Cord Med 39(2):212–219. https://doi.org/10.1179/2045772315Y.0000000047
Naziroglu M, Uguz AC, Ismailoglu O, Cig B, Ozgul C, Borcak M (2013) Role of TRPM2 cation channels in dorsal root ganglion of rats after experimental spinal cord injury. Muscle Nerve 48(6):945–950. https://doi.org/10.1002/mus.23844
Nees TA, Tappe-Theodor A, Sliwinski C, Motsch M, Rupp R, Kuner R, Weidner N, Blesch A (2016) Early-onset treadmill training reduces mechanical allodynia and modulates calcitonin gene-related peptide fiber density in lamina III/IV in a mouse model of spinal cord contusion injury. Pain 157(3):687–697. https://doi.org/10.1097/j.pain.0000000000000422
Nishio N, Taniguchi W, Sugimura YK, Takiguchi N, Yamanaka M, Kiyoyuki Y, Yamada H, Miyazaki N, Yoshida M, Nakatsuka T (2013) Reactive oxygen species enhance excitatory synaptic transmission in rat spinal dorsal horn neurons by activating TRPA1 and TRPV1 channels. Neuroscience 247:201–212. https://doi.org/10.1016/j.neuroscience.2013.05.023
Noga BR, Pinzon A, Mesigil RP, Hentall ID (2004) Steady-state levels of monoamines in the rat lumbar spinal cord: spatial mapping and the effect of acute spinal cord injury. J Neurophysiol 92(1):567–577. https://doi.org/10.1152/jn.01035.2003
Oatway MA, Chen Y, Weaver LC (2004) The 5-HT3 receptor facilitates at-level mechanical allodynia following spinal cord injury. Pain 110(1–2):259–268. https://doi.org/10.1016/j.pain.2004.03.040
Odem MA, Bavencoffe AG, Cassidy RM, Lopez ER, Tian J, Dessauer CW, Walters ET (2018) Isolated nociceptors reveal multiple specializations for generating irregular ongoing activity associated with ongoing pain. Pain 159(11):2347–2362. https://doi.org/10.1097/j.pain.0000000000001341
Ondarza AB, Ye Z, Hulsebosch CE (2003) Direct evidence of primary afferent sprouting in distant segments following spinal cord injury in the rat: colocalization of GAP-43 and CGRP. Exp Neurol 184(1):373–380
Ozaki S, Snider WD (1997) Initial trajectories of sensory axons toward laminar targets in the developing mouse spinal cord. J Comp Neurol 380(2):215–229
Ozdemir US, Naziroglu M, Senol N, Ghazizadeh V (2016) Hypericum perforatum attenuates spinal cord injury-induced oxidative stress and apoptosis in the dorsal root ganglion of rats: involvement of TRPM2 and TRPV1 channels. Mol Neurobiol 53(6):3540–3551. https://doi.org/10.1007/s12035-015-9292-1
Ozturk AM, Sozbilen MC, Sevgili E, Dagci T, Ozyalcin H, Armagan G (2018) Epidermal growth factor regulates apoptosis and oxidative stress in a rat model of spinal cord injury. Injury 49(6):1038–1045. https://doi.org/10.1016/j.injury.2018.03.021
Papa S, Rossi F, Ferrari R, Mariani A, De Paola M, Caron I, Fiordaliso F, Bisighini C, Sammali E, Colombo C, Gobbi M, Canovi M, Lucchetti J, Peviani M, Morbidelli M, Forloni G, Perale G, Moscatelli D, Veglianese P (2013) Selective nanovector mediated treatment of activated proinflammatory microglia/macrophages in spinal cord injury. ACS Nano 7(11):9881–9895. https://doi.org/10.1021/nn4036014
Park A, Uddin O, Li Y, Masri R, Keller A (2018) Pain after spinal cord injury is associated with abnormal presynaptic inhibition in the posterior nucleus of the thalamus. J Pain 19(7):727. https://doi.org/10.1016/j.jpain.2018.02.002
Paulson PE, Gorman AL, Yezierski RP, Casey KL, Morrow TJ (2005) Differences in forebrain activation in two strains of rat at rest and after spinal cord injury. Exp Neurol 196(2):413–421. https://doi.org/10.1016/j.expneurol.2005.08.015
Pelisch N, Gomes C, Nally JM, Petruska JC, Stirling DP (2017) Differential expression of ryanodine receptor isoforms after spinal cord injury. Neurosci Lett 660:51–56. https://doi.org/10.1016/j.neulet.2017.09.018
Qiao LY, Vizzard MA (2005) Spinal cord injury-induced expression of TrkA, TrkB, phosphorylated CREB, and c-Jun in rat lumbosacral dorsal root ganglia. J Comp Neurol 482(2):142–154. https://doi.org/10.1002/cne.20394
Rasband MN, Park EW, Vanderah TW, Lai J, Porreca F, Trimmer JS (2001) Distinct potassium channels on pain-sensing neurons. Proc Natl Acad Sci USA 98(23):13373–13378. https://doi.org/10.1073/pnas.231376298
Ravenscroft AJ (2000) Chronic pain after spinal cord injury: a survey of practice in spinal injury units in the USA. Spinal Cord 38(11):658–660
Redondo-Castro E, Garcia-Alias G, Navarro X (2013) Plastic changes in lumbar segments after thoracic spinal cord injuries in adult rats: an integrative view of spinal nociceptive dysfunctions. Restor Neurol Neurosci 31(4):411–430. https://doi.org/10.3233/RNN-120291
Rintala DH, Loubser PG, Castro J, Hart KA, Fuhrer MJ (1998) Chronic pain in a community-based sample of men with spinal cord injury: prevalence, severity, and relationship with impairment, disability, handicap, and subjective well-being. Arch Phys Med Rehabil 79(6):604–614
Rintala DH, Holmes SA, Fiess RN, Courtade D, Loubser PG (2005) Prevalence and characteristics of chronic pain in veterans with spinal cord injury. J Rehabil Res Dev 42(5):573–584
Ritter DM, Zemel BM, Hala TJ, O'Leary ME, Lepore AC, Covarrubias M (2015) Dysregulation of Kv3.4 channels in dorsal root ganglia following spinal cord injury. J Neurosci 35(3):1260–1273. https://doi.org/10.1523/JNEUROSCI.1594-14.2015
Rivlin AS, Tator CH (1978) Effect of duration of acute spinal cord compression in a new acute cord injury model in the rat. Surg Neurol 10(1):38–43
Saab CY, Hains BC (2009) Remote neuroimmune signaling: a long-range mechanism of nociceptive network plasticity. Trends Neurosci 32(2):110–117. https://doi.org/10.1016/j.tins.2008.11.004
Sanchez-Brualla I, Boulenguez P, Brocard C, Liabeuf S, Viallat-Lieutaud A, Navarro X, Udina E, Brocard F (2018) Activation of 5-HT2A receptors restores KCC2 function and reduces neuropathic pain after spinal cord injury. Neuroscience 387:48–57. https://doi.org/10.1016/j.neuroscience.2017.08.033
Schneider LE, Henley KY, Turner OA, Pat B, Niedzielko TL, Floyd CL (2017) Application of the rat grimace scale as a marker of supraspinal pain sensation after cervical spinal cord injury. J Neurotrauma 34(21):2982–2993. https://doi.org/10.1089/neu.2016.4665
Sekhon LH, Fehlings MG (2001) Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine 26(24 Suppl):S2–S12
Shiao R, Lee-Kubli CA (2018) Neuropathic pain after spinal cord injury: challenges and research perspectives. Neurotherapeutics. https://doi.org/10.1007/s13311-018-0633-4
Siddall PJ, Taylor DA, McClelland JM, Rutkowski SB, Cousins MJ (1999) Pain report and the relationship of pain to physical factors in the first 6 months following spinal cord injury. Pain 81(1–2):187–197
Siddall PJ, McClelland JM, Rutkowski SB, Cousins MJ (2003) A longitudinal study of the prevalence and characteristics of pain in the first 5 years following spinal cord injury. Pain 103(3):249–257
Sydekum E, Baltes C, Ghosh A, Mueggler T, Schwab ME, Rudin M (2009) Functional reorganization in rat somatosensory cortex assessed by fMRI: elastic image registration based on structural landmarks in fMRI images and application to spinal cord injured rats. Neuroimage 44(4):1345–1354. https://doi.org/10.1016/j.neuroimage.2008.10.015
Syre PP, Weisshaar CL, Winkelstein BA (2014) Sustained neuronal hyperexcitability is evident in the thalamus after a transient cervical radicular injury. Spine 39(15):E870–E877. https://doi.org/10.1097/BRS.0000000000000392
Takahashi R, Yoshizawa T, Yunoki T, Tyagi P, Naito S, de Groat WC, Yoshimura N (2013) Hyperexcitability of bladder afferent neurons associated with reduction of Kv1.4 alpha-subunit in rats with spinal cord injury. J Urol 190(6):2296–2304. https://doi.org/10.1016/j.juro.2013.07.058
Tashima R, Koga K, Sekine M, Kanehisa K, Kohro Y, Tominaga K, Matsushita K, Tozaki-Saitoh H, Fukazawa Y, Inoue K, Yawo H, Furue H, Tsuda M (2018) Optogenetic activation of non-nociceptive abeta fibers induces neuropathic pain-like sensory and emotional behaviors after nerve injury in rats. eNeuro. https://doi.org/10.1523/ENEURO.0450-17.2018.
Tobaldini G, Sardi NF, Guilhen VA, Fischer L (2018) Pain inhibits pain: an ascending-descending pain modulation pathway linking mesolimbic and classical descending mechanisms. Mol Neurobiol. https://doi.org/10.1007/s12035-018-1116-7
Troster P, Haseleu J, Petersen J, Drees O, Schmidtko A, Schwaller F, Lewin GR, Ter-Avetisyan G, Winter Y, Peters S, Feil S, Feil R, Rathjen FG, Schmidt H (2018) The absence of sensory axon bifurcation affects nociception and termination fields of afferents in the spinal cord. Front Mol Neurosci 11:19. https://doi.org/10.3389/fnmol.2018.00019
van Gorp S, Kessels AG, Joosten EA, van Kleef M, Patijn J (2015) Pain prevalence and its determinants after spinal cord injury: a systematic review. Eur J Pain 19(1):5–14. https://doi.org/10.1002/ejp.522
Vaziri ND, Lee YS, Lin CY, Lin VW, Sindhu RK (2004) NAD(P)H oxidase, superoxide dismutase, catalase, glutathione peroxidase and nitric oxide synthase expression in subacute spinal cord injury. Brain Res 995(1):76–83
Vierck CJ, Baastrup C, Maersk-Moller C, Roth M, Cannon RL, Finnerup NB, Yezierski RP (2015) A preclinical model of hyperalgesia following spinal stenosis/compression. Eur J Pain 19(8):1158–1167. https://doi.org/10.1002/ejp.640
Vogel C, Rukwied R, Stockinger L, Schley M, Schmelz M, Schleinzer W, Konrad C (2017) Functional characterization of at-level hypersensitivity in patients with spinal cord injury. J Pain 18(1):66–78. https://doi.org/10.1016/j.jpain.2016.10.003
Vuckovic A, Jarjees M, Abul Hasan M, Miyakoshi M, Fraser M (2018) Central neuropathic pain in paraplegia alters movement related potentials. Clin Neurophysiol 129(8):1669–1679. https://doi.org/10.1016/j.clinph.2018.05.020
Walters ET (2012) Nociceptors as chronic drivers of pain and hyperreflexia after spinal cord injury: an adaptive-maladaptive hyperfunctional state hypothesis. Front Physiol 3:309. https://doi.org/10.3389/fphys.2012.00309
Wang G, Thompson SM (2008) Maladaptive homeostatic plasticity in a rodent model of central pain syndrome: thalamic hyperexcitability after spinothalamic tract lesions. J Neurosci 28(46):11959–11969. https://doi.org/10.1523/JNEUROSCI.3296-08.2008
Wang J, Kawamata M, Namiki A (2005) Changes in properties of spinal dorsal horn neurons and their sensitivity to morphine after spinal cord injury in the rat. Anesthesiology 102(1):152–164
Watanabe M, Narita M, Hamada Y, Yamashita A, Tamura H, Ikegami D, Kondo T, Shinzato T, Shimizu T, Fukuchi Y, Muto A, Okano H, Yamanaka A, Tawfik VL, Kuzumaki N, Navratilova E, Porreca F, Narita M (2018) Activation of ventral tegmental area dopaminergic neurons reverses pathological allodynia resulting from nerve injury or bone cancer. Mol Pain 14:1744806918756406. https://doi.org/10.1177/1744806918756406
Watkins LR, Maier SF (2002) Beyond neurons: evidence that immune and glial cells contribute to pathological pain states. Physiol Rev 82(4):981–1011. https://doi.org/10.1152/physrev.00011.2002
Weisshaar CL, Kras JV, Pall PS, Kartha S, Winkelstein BA (2017) Ablation of IB4 non-peptidergic afferents in the rat facet joint prevents injury-induced pain and thalamic hyperexcitability via supraspinal glutamate transporters. Neurosci Lett 655:82–89. https://doi.org/10.1016/j.neulet.2017.07.006
Whitt JL, Masri R, Pulimood NS, Keller A (2013) Pathological activity in mediodorsal thalamus of rats with spinal cord injury pain. J Neurosci 33(9):3915–3926. https://doi.org/10.1523/JNEUROSCI.2639-12.2013
Widerstrom-Noga E (2017) Neuropathic pain and spinal cord injury: phenotypes and pharmacological management. Drugs 77(9):967–984. https://doi.org/10.1007/s40265-017-0747-8
Widerstrom-Noga E, Pattany PM, Cruz-Almeida Y, Felix ER, Perez S, Cardenas DD, Martinez-Arizala A (2013) Metabolite concentrations in the anterior cingulate cortex predict high neuropathic pain impact after spinal cord injury. Pain 154(2):204–212. https://doi.org/10.1016/j.pain.2012.07.022
Widerstrom-Noga E, Felix ER, Adcock JP, Escalona M, Tibbett J (2016) Multidimensional neuropathic pain phenotypes after spinal cord injury. J Neurotrauma 33(5):482–492. https://doi.org/10.1089/neu.2015.4040
Willis WD, Westlund KN (1997) Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol 14(1):2–31
Wrigley PJ, Press SR, Gustin SM, Macefield VG, Gandevia SC, Cousins MJ, Middleton JW, Henderson LA, Siddall PJ (2009) Neuropathic pain and primary somatosensory cortex reorganization following spinal cord injury. Pain 141(1–2):52–59. https://doi.org/10.1016/j.pain.2008.10.007
Wu J, Raver C, Piao C, Keller A, Faden AI (2013) Cell cycle activation contributes to increased neuronal activity in the posterior thalamic nucleus and associated chronic hyperesthesia after rat spinal cord contusion. Neurotherapeutics 10(3):520–538. https://doi.org/10.1007/s13311-013-0198-1
Wu J, Zhao Z, Sabirzhanov B, Stoica BA, Kumar A, Luo T, Skovira J, Faden AI (2014) Spinal cord injury causes brain inflammation associated with cognitive and affective changes: role of cell cycle pathways. J Neurosci 34(33):10989–11006. https://doi.org/10.1523/JNEUROSCI.5110-13.2014
Wu Z, Li L, Xie F, Du J, Zuo Y, Frost JA, Carlton SM, Walters ET, Yang Q (2017) Activation of KCNQ channels suppresses spontaneous activity in dorsal root ganglion neurons and reduces chronic pain after spinal cord injury. J Neurotrauma 34(6):1260–1270. https://doi.org/10.1089/neu.2016.4789
Xiong W, Ping X, Ripsch MS, Chavez GSC, Hannon HE, Jiang K, Bao C, Jadhav V, Chen L, Chai Z, Ma C, Wu H, Feng J, Blesch A, White FA, Jin X (2017) Enhancing excitatory activity of somatosensory cortex alleviates neuropathic pain through regulating homeostatic plasticity. Sci Rep 7(1):12743. https://doi.org/10.1038/s4159s8-017-12972-6
Yague JG, Foffani G, Aguilar J (2011) Cortical hyperexcitability in response to preserved spinothalamic inputs immediately after spinal cord hemisection. Exp Neurol 227(2):252–263. https://doi.org/10.1016/j.expneurol.2010.11.011
Yague JG, Humanes-Valera D, Aguilar J, Foffani G (2014) Functional reorganization of the forepaw cortical representation immediately after thoracic spinal cord hemisection in rats. Exp Neurol 257:19–24. https://doi.org/10.1016/j.expneurol.2014.03.015
Yang G, Tang WY (2017) Resistance of interleukin-6 to the extracellular inhibitory environment promotes axonal regeneration and functional recovery following spinal cord injury. Int J Mol Med 39(2):437–445. https://doi.org/10.3892/ijmm.2017.2848
Yang Q, Wu Z, Hadden JK, Odem MA, Zuo Y, Crook RJ, Frost JA, Walters ET (2014) Persistent pain after spinal cord injury is maintained by primary afferent activity. J Neurosci 34(32):10765–10769. https://doi.org/10.1523/JNEUROSCI.5316-13.2014
Yezierski RP, Liu S, Ruenes GL, Kajander KJ, Brewer KL (1998) Excitotoxic spinal cord injury: behavioral and morphological characteristics of a central pain model. Pain 75(1):141–155
Zeilig G, Enosh S, Rubin-Asher D, Lehr B, Defrin R (2012) The nature and course of sensory changes following spinal cord injury: predictive properties and implications on the mechanism of central pain. Brain 135(Pt 2):418–430. https://doi.org/10.1093/brain/awr270
Zemel BM, Muqeem T, Brown EV, Goulao M, Urban MW, Tymanskyj SR, Lepore AC, Covarrubias M (2017) Calcineurin dysregulation underlies spinal cord injury-induced K(+) channel dysfunction in DRG neurons. J Neurosci 37(34):8256–8272. https://doi.org/10.1523/JNEUROSCI.0434-17.2017
Zhang G, Yang P (2017) Bioinformatics genes and pathway analysis for chronic neuropathic pain after spinal cord injury. Biomed Res Int 2017:6423021. https://doi.org/10.1155/2017/6423021
Zhang H, Xie W, Xie Y (2005) Spinal cord injury triggers sensitization of wide dynamic range dorsal horn neurons in segments rostral to the injury. Brain Res 1055(1–2):103–110. https://doi.org/10.1016/j.brainres.2005.06.072
Zhou C, Luo ZD (2014) Electrophysiological characterization of spinal neuron sensitization by elevated calcium channel alpha-2-delta-1 subunit protein. Eur J Pain 18(5):649–658. https://doi.org/10.1002/j.1532-2149.2013.00416.x
Zhuo M (2011) Cortical plasticity as a new endpoint measurement for chronic pain. Mol Pain 7:54. https://doi.org/10.1186/1744-8069-7-54
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This work was supported by the National Research Foundation of Korea (NRF-2017R1D1A3B03035303).
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Kang, J., Cho, S.S., Kim, H.Y. et al. Regional Hyperexcitability and Chronic Neuropathic Pain Following Spinal Cord Injury. Cell Mol Neurobiol 40, 861–878 (2020). https://doi.org/10.1007/s10571-020-00785-7
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DOI: https://doi.org/10.1007/s10571-020-00785-7