Purinergic Modulation of Spinal Neuroglial Maladaptive Plasticity Following Peripheral Nerve Injury

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• 作者：Giovanni Cirillo ; Anna Maria Colangelo ; Miluscia Berbenni…
• 关键词：Reactive astrocytosis ; Neuroglial network ; Calcium imaging ; Synaptic homeostasis ; Maladaptive plasticity ; Nerve injury
• 刊名：Molecular Neurobiology
• 出版年：2015
• 出版时间：December 2015
• 年：2015
• 卷：52
• 期：3
• 页码：1440-1457
• 全文大小：5,557 KB
• 参考文献：1.Pascual O, Ben AS, Rostaing P, Triller A, Bessis A (2012) Microglia activation triggers astrocyte-mediated modulation of excitatory neurotransmission. Proc Natl Acad Sci U S A 109:E197鈥揈205PubMed Central CrossRef PubMed
  2.Perea G, Araque A (2007) Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317:1083鈥?086CrossRef PubMed
  3.Angulo MC, Kozlov AS, Charpak S, Audinat E (2004) Glutamate released from glial cells synchronizes neuronal activity in the hippocampus. J Neurosci 24:6920鈥?927CrossRef PubMed
  4.Fellin T, Pascual O, Gobbo S, Pozzan T, Haydon PG, Carmignoto G (2004) Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43:729鈥?43CrossRef PubMed
  5.Haydon PG (2001) GLIA: listening and talking to the synapse. Nat Rev Neurosci 2:185鈥?93CrossRef PubMed
  6.Giaume C, Koulakoff A, Roux L, Holcman D, Rouach N (2010) Astroglial networks: a step further in neuroglial and gliovascular interactions. Nat Rev Neurosci 11:87鈥?9CrossRef PubMed
  7.Verkhratsky A (2010) Physiology of neuronal-glial networking. Neurochem Int 57:332鈥?43CrossRef PubMed
  8.Allen NJ, Barres BA (2009) Neuroscience: glia鈥攎ore than just brain glue. Nature 457:675鈥?77CrossRef PubMed
  9.Cirillo G, Colangelo AM, Bianco MR, Cavaliere C, Zaccaro L, Sarmientos P, Alberghina L, Papa M (2012) BB14, a nerve growth factor (NGF)-like peptide shown to be effective in reducing reactive astrogliosis and restoring synaptic homeostasis in a rat model of peripheral nerve injury. Biotechnol Adv 30:223鈥?32CrossRef PubMed
  10.Cirillo G, Bianco MR, Colangelo AM, Cavaliere C, De Luca D, Zaccaro L, Alberghina L, Papa M (2011) Reactive astrocytosis-induced perturbation of synaptic homeostasis is restored by nerve growth factor. Neurobiol Dis 41:630鈥?39CrossRef PubMed
  11.Papa M, De Luca C, Petta F, Alberghina L, Cirillo G (2014) Astrocyte-neuron interplay in maladaptive plasticity. Neurosci Biobehav Rev 42C:35鈥?4CrossRef
  12.Colangelo AM, Cirillo G, Lavitrano ML, Alberghina L, Papa M (2012) Targeting reactive astrogliosis by novel biotechnological strategies. Biotechnol Adv 30:261鈥?71CrossRef PubMed
  13.Gwak YS, Hulsebosch CE (2011) GABA and central neuropathic pain following spinal cord injury. Neuropharmacology 60:799鈥?08PubMed Central CrossRef PubMed
  14.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 234:362鈥?72PubMed Central CrossRef PubMed
  15.Hulsebosch CE (2008) Gliopathy ensures persistent inflammation and chronic pain after spinal cord injury. Exp Neurol 214:6鈥?PubMed Central CrossRef PubMed
  16.Lobsiger CS, Cleveland DW (2007) Glial cells as intrinsic components of non-cell-autonomous neurodegenerative disease. Nat Neurosci 10:1355鈥?360PubMed Central CrossRef PubMed
  17.Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50:427鈥?34CrossRef PubMed
  18.Milligan ED, Watkins LR (2009) Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10:23鈥?6PubMed Central CrossRef PubMed
  19.Colangelo AM, Bianco MR, Vitagliano L, Cavaliere C, Cirillo G, De Gioia L, Diana D, Colombo D, Redaelli C, Zaccaro L, Morelli G, Papa M, Sarmientos P, Alberghina L, Martegani E (2008) A new nerve growth factor-mimetic peptide active on neuropathic pain in rats. J Neurosci 28:2698鈥?709CrossRef PubMed
  20.Cirillo G, Cavaliere C, Bianco MR, De Simone A, Colangelo AM, Sellitti S, Alberghina L, Papa M (2010) Intrathecal NGF administration reduces reactive astrocytosis and changes neurotrophin receptors expression pattern in a rat model of neuropathic pain. Cell Mol Neurobiol 30:51鈥?2CrossRef PubMed
  21.Inoue K, Tsuda M (2012) Purinergic systems, neuropathic pain and the role of microglia. Exp Neurol 234:293鈥?01CrossRef PubMed
  22.Gourine AV, Dale N, Llaudet E, Poputnikov DM, Spyer KM, Gourine VN (2007) Release of ATP in the central nervous system during systemic inflammation: real-time measurement in the hypothalamus of conscious rabbits. J Physiol 585:305鈥?16PubMed Central CrossRef PubMed
  23.Khakh BS, North RA (2006) P2X receptors as cell-surface ATP sensors in health and disease. Nature 442:527鈥?32CrossRef PubMed
  24.Peng W, Cotrina ML, Han X, Yu H, Bekar L, Blum L, Takano T, Tian GF, Goldman SA, Nedergaard M (2009) Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury. Proc Natl Acad Sci U S A 106:12489鈥?2493PubMed Central CrossRef PubMed
  25.Illes P, Verkhratsky A, Burnstock G, Franke H (2012) P2X receptors and their roles in astroglia in the central and peripheral nervous system. Neuroscientist 18:422鈥?38CrossRef PubMed
  26.Koles L, Leichsenring A, Rubini P, Illes P (2011) P2 receptor signaling in neurons and glial cells of the central nervous system. Adv Pharmacol 61:441鈥?93CrossRef PubMed
  27.Wang X, Arcuino G, Takano T, Lin J, Peng WG, Wan P, Li P, Xu Q, Liu QS, Goldman SA, Nedergaard M (2004) P2X7 receptor inhibition improves recovery after spinal cord injury. Nat Med 10:821鈥?27CrossRef PubMed
  28.Zhou D, Chen ML, Zhang YQ, Zhao ZQ (2010) Involvement of spinal microglial P2X7 receptor in generation of tolerance to morphine analgesia in rats. J Neurosci 30:8042鈥?047CrossRef PubMed
  29.Hamilton N, Vayro S, Kirchhoff F, Verkhratsky A, Robbins J, Gorecki DC, Butt AM (2008) Mechanisms of ATP- and glutamate-mediated calcium signaling in white matter astrocytes. Glia 56:734鈥?49CrossRef PubMed
  30.Narcisse L, Scemes E, Zhao Y, Lee SC, Brosnan CF (2005) The cytokine IL-1beta transiently enhances P2X7 receptor expression and function in human astrocytes. Glia 49:245鈥?58PubMed Central CrossRef PubMed
  31.Rodriguez-Zayas AE, Torrado AI, Rosas OR, Santiago JM, Figueroa JD, Miranda JD (2012) Blockade of P2 nucleotide receptors after spinal cord injury reduced the gliotic response and spared tissue. J Mol Neurosci 46:167鈥?76PubMed Central CrossRef PubMed
  32.Rodriguez-Zayas AE, Torrado AI, Miranda JD (2010) P2Y2 receptor expression is altered in rats after spinal cord injury. Int J Dev Neurosci 28:413鈥?21PubMed Central CrossRef PubMed
  33.Shiratori M, Tozaki-Saitoh H, Yoshitake M, Tsuda M, Inoue K (2010) P2X7 receptor activation induces CXCL2 production in microglia through NFAT and PKC/MAPK pathways. J Neurochem 114:810鈥?19CrossRef PubMed
  34.Delarasse C, Auger R, Gonnord P, Fontaine B, Kanellopoulos JM (2011) The purinergic receptor P2X7 triggers alpha-secretase-dependent processing of the amyloid precursor protein. J Biol Chem 286:2596鈥?606PubMed Central CrossRef PubMed
  35.Hanley PJ, Kronlage M, Kirschning C, del RA, Di VF, Leipziger J, Chessell IP, Sargin S, Filippov MA, Lindemann O, Mohr S, Konigs V, Schillers H, Bahler M, Schwab A (2012) Transient P2X7 receptor activation triggers macrophage death independent of Toll-like receptors 2 and 4, caspase-1, and pannexin-1 proteins. J Biol Chem 287:10650鈥?0663
  36.Bianco MR, Cirillo G, Petrosino V, Marcello L, Soleti A, Merizzi G, Cavaliere C, Papa M (2012) Neuropathic pain and reactive gliosis are reversed by dialdehydic compound in neuropathic pain rat models. Neurosci Lett 530:85鈥?0CrossRef PubMed
  37.Beigi RD, Kertesy SB, Aquilina G, Dubyak GR (2003) Oxidized ATP (oATP) attenuates proinflammatory signaling via P2 receptor-independent mechanisms. Br J Pharmacol 140:507鈥?19PubMed Central CrossRef PubMed
  38.Decosterd I, Woolf CJ (2000) Spared nerve injury: an animal model of persistent peripheral neuropathic pain. Pain 87:149鈥?58CrossRef PubMed
  39.Johannssen HC, Helmchen F (2010) In vivo Ca2+ imaging of dorsal horn neuronal populations in mouse spinal cord. J Physiol 588:3397鈥?402PubMed Central CrossRef PubMed
  40.Davalos D, Lee JK, Smith WB, Brinkman B, Ellisman MH, Zheng B, Akassoglou K (2008) Stable in vivo imaging of densely populated glia, axons and blood vessels in the mouse spinal cord using two-photon microscopy. J Neurosci Methods 169:1鈥?PubMed Central CrossRef PubMed
  41.Stosiek C, Garaschuk O, Holthoff K, Konnerth A (2003) In vivo two-photon calcium imaging of neuronal networks. Proc Natl Acad Sci U S A 100:7319鈥?324PubMed Central CrossRef PubMed
  42.Golshani P, Portera-Cailliau C (2008) In vivo 2-photon calcium imaging in layer 2/3 of mice. J Vis Exp
  43.Nimmerjahn A, Kirchhoff F, Kerr JN, Helmchen F (2004) Sulforhodamine 101 as a specific marker of astroglia in the neocortex in vivo. Nat Methods 1:31鈥?7CrossRef PubMed
  44.Sanganahalli BG, Herman P, Blumenfeld H, Hyder F (2009) Oxidative neuroenergetics in event-related paradigms. J Neurosci 29:1707鈥?718PubMed Central CrossRef PubMed
  45.Cirillo G, De Luca D, Papa M (2012) Calcium imaging of living astrocytes in the mouse spinal cord following sensory stimulation. Neural Plast 2012:425818PubMed Central PubMed
  46.Kuchibhotla KV, Lattarulo CR, Hyman BT, Bacskai BJ (2009) Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323:1211鈥?215PubMed Central CrossRef PubMed
  47.Hargreaves K, Dubner R, Brown F, Flores C, Joris J (1988) A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32:77鈥?8CrossRef PubMed
  48.Papa M, Boscia F, Canitano A, Castaldo P, Sellitti S, Annunziato L, Taglialatela M (2003) Expression pattern of the ether-a-gogo-related (ERG) K+ channel-encoding genes ERG1, ERG2, and ERG3 in the adult rat central nervous system. J Comp Neurol 466:119鈥?35CrossRef PubMed
  49.Gullo F, Maffezzoli A, Dossi E, Wanke E (2009) Short-latency cross- and autocorrelation identify clusters of interacting cortical neurons recorded from multi-electrode array. J Neurosci Methods 181:186鈥?98CrossRef PubMed
  50.Consonni A, Morara S, Codazzi F, Grohovaz F, Zacchetti D (2011) Inhibition of lipopolysaccharide-induced microglia activation by calcitonin gene related peptide and adrenomedullin. Mol Cell Neurosci 48:151鈥?60PubMed Central CrossRef PubMed
  51.Bianco MR, Berbenni M, Amara F, Viggiani S, Fragni M, Galimberti V, Colombo D, Cirillo G, Papa M, Alberghina L, Colangelo AM (2011) Cross-talk between cell cycle induction and mitochondrial dysfunction during oxidative stress and nerve growth factor withdrawal in differentiated PC12 cells. J Neurosci Res 89:1302鈥?315CrossRef PubMed
  52.Cavaliere C, Cirillo G, Bianco MR, Rossi F, De Novellis V, Maione S, Papa M (2007) Gliosis alters expression and uptake of spinal glial amino acid transporters in a mouse neuropathic pain model. Neuron Glia Biol 3:141鈥?53CrossRef PubMed
  53.Robel S, Berninger B, G枚tz M (2011) The stem cell potential of glia: lessons from reactive gliosis. Nat Rev Neurosci 12:88鈥?04CrossRef PubMed
  54.Bachis A, Colangelo AM, Vicini S, Doe PP, De Bernardi MA, Brooker G, Mocchetti I (2001) Interleukin-10 prevents glutamate-mediated cerebellar granule cell death by blocking caspase-3-like activity. J Neurosci 21(9):3104鈥?112PubMed
  55.Henneberger C, Rusakov DA (2010) Synaptic plasticity and Ca2+ signalling in astrocytes. Neuron Glia Biol 1鈥?
  56.Hamilton NB, Attwell D (2010) Do astrocytes really exocytose neurotransmitters? Nat Rev Neurosci 11:227鈥?38CrossRef PubMed
  57.Ni Y, Parpura V (2009) Dual regulation of Ca2+-dependent glutamate release from astrocytes: vesicular glutamate transporters and cytosolic glutamate levels. Glia 57:1296鈥?305PubMed Central CrossRef PubMed
  58.Winship IR, Plaa N, Murphy TH (2007) Rapid astrocyte calcium signals correlate with neuronal activity and onset of the hemodynamic response in vivo. J Neurosci 27:6268鈥?272CrossRef PubMed
  59.Jiang M, Chen G (2009) Ca2+ regulation of dynamin-independent endocytosis in cortical astrocytes. J Neurosci 29:8063鈥?074CrossRef PubMed
  60.Bardoni R, Ghirri A, Zonta M, Betelli C, Vitale G, Ruggieri V, Sandrini M, Carmignoto G (2010) Glutamate-mediated astrocyte-to-neuron signalling in the rat dorsal horn. J Physiol 588:831鈥?46PubMed Central CrossRef PubMed
  61.Koizumi S (2010) Synchronization of Ca2+ oscillations: involvement of ATP release in astrocytes. FEBS J 277:286鈥?92CrossRef PubMed
  62.Gwak YS, Hulsebosch CE (2009) Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat. Neuroscience 161:895鈥?03PubMed Central CrossRef PubMed
  63.Wang W, Wang W, Mei X, Huang J, Wei Y, Wang Y, Wu S, Li Y (2009) Crosstalk between spinal astrocytes and neurons in nerve injury-induced neuropathic pain. PLoS One 4:e6973PubMed Central CrossRef PubMed
  64.Fellin T, Carmignoto G (2004) Neurone-to-astrocyte signalling in the brain represents a distinct multifunctional unit. J Physiol 559:3鈥?5PubMed Central CrossRef PubMed
  65.Haydon PG, Carmignoto G (2006) Astrocyte control of synaptic transmission and neurovascular coupling. Physiol Rev 86:1009鈥?0031CrossRef PubMed
  66.Trang T, Beggs S, Salter MW (2012) ATP receptors gate microglia signaling in neuropathic pain. Exp Neurol 234:354鈥?61PubMed Central CrossRef PubMed
  67.Tsuda M, Tozaki-Saitoh H, Inoue K (2012) Purinergic system, microglia and neuropathic pain. Curr Opin Pharmacol 12:74鈥?9CrossRef PubMed
  68.Pankratov Y, Lalo U, Krishtal OA, Verkhratsky A (2009) P2X receptors and synaptic plasticity. Neuroscience 158:137鈥?48CrossRef PubMed
  69.Nakatsuka T, Tsuzuki K, Ling JX, Sonobe H, Gu JG (2003) Distinct roles of P2X receptors in modulating glutamate release at different primary sensory synapses in rat spinal cord. J Neurophysiol 89:3243鈥?252CrossRef PubMed
  70.He WJ, Cui J, Du L, Zhao YD, Burnstock G, Zhou HD, Ruan HZ (2012) Spinal P2X(7) receptor mediates microglia activation-induced neuropathic pain in the sciatic nerve injury rat model. Behav Brain Res 226:163鈥?70CrossRef PubMed
  71.Choi HB, Ryu JK, Kim SU, McLarnon JG (2007) Modulation of the purinergic P2X7 receptor attenuates lipopolysaccharide-mediated microglial activation and neuronal damage in inflamed brain. J Neurosci 27:4957鈥?968CrossRef PubMed
  72.Neary JT, Kang Y, Shi YF, Tran MD, Wanner IB (2006) P2 receptor signalling, proliferation of astrocytes, and expression of molecules involved in cell-cell interactions. Novartis Found Symp 276:131鈥?43CrossRef PubMed
  73.Neary JT, Kang Y (2005) Signaling from P2 nucleotide receptors to protein kinase cascades induced by CNS injury: implications for reactive gliosis and neurodegeneration. Mol Neurobiol 31:95鈥?03CrossRef PubMed
  74.Fulgenzi A, Dell鈥橝ntonio G, Foglieni C, Dal Cin E, Ticozzi P, Franzone JS, Ferrero ME (2005) Inhibition of chemokine expression in rat inflamed paws by systemic use of the antihyperalgesic oxidized ATP. BMC Immunol 6:18PubMed Central CrossRef PubMed
  75.Bonin RP, De Koninck Y (2014) A spinal analog of memory reconsolidation enables reversal of hyperalgesia. Nat Neurosci 17(8):1043鈥?045CrossRef PubMed
  76.Chessell IP, Hatcher JP, Bountra C, Michel AD, Hughes JP, Green P, Egerton J, Murfin M, Richardson J, Peck WL, Grahames CB, Casula MA, Yiangou Y, Birch R, Anand P, Buell GN (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114:386鈥?96CrossRef PubMed
  77.Kim SY, Moon JH, Lee HG, Kim SU, Lee YB (2007) ATP released from beta-amyloid-stimulated microglia induces reactive oxygen species production in an autocrine fashion. Exp Mol Med 39:820鈥?27CrossRef PubMed
  78.Liu YP, Yang CS, Chen MC, Sun SH, Tzeng SF (2010) Ca(2+)-dependent reduction of glutamate aspartate transporter GLAST expression in astrocytes by P2X(7) receptor-mediated phosphoinositide 3-kinase signaling. J Neurochem 113:213鈥?27CrossRef PubMed
  79.Deuchars SA, Atkinson L, Brooke RE, Musa H, Milligan CJ, Batten TF, Buckley NJ, Parson SH, Deuchars J (2001) Neuronal P2X7 receptors are targeted to presynaptic terminals in the central and peripheral nervous systems. J Neurosci 21:7143鈥?152PubMed
  80.Sperlagh B, Kofalvi A, Deuchars J, Atkinson L, Milligan CJ, Buckley NJ, Vizi ES (2002) Involvement of P2X7 receptors in the regulation of neurotransmitter release in the rat hippocampus. J Neurochem 81:1196鈥?211CrossRef PubMed
  81.Anderson CM, Nedergaard M (2006) Emerging challenges of assigning P2X7 receptor function and immunoreactivity in neurons. Trends Neurosci 29:257鈥?62CrossRef PubMed
  82.Cavaliere C, Cirillo G, Bianco MR, Adriani W, De Simone A, Leo D, Perrone-Capano C, Papa M (2012) Methylphenidate administration determines enduring changes in neuroglial network in rats. Eur Neuropsychopharmacol 22:53鈥?3CrossRef PubMed
  83.Leo D, Adriani W, Cavaliere C, Cirillo G, Marco EM, Romano E, Di Porzio U, Papa M, Perrone-Capano C, Laviola G (2009) Methylphenidate to adolescent rats drives enduring changes of accumbal Htr7 expression: implications for impulsive behavior and neuronal morphology. Genes Brain Behav 8:356鈥?68CrossRef PubMed
  84.Musholt K, Cirillo G, Cavaliere C, Bianco MR, Bock J, Helmeke C, Braun K, Papa M (2009) Neonatal separation stress reduces glial fibrillary acidic protein- and S100beta-immunoreactive astrocytes in the rat medial precentral cortex. Dev Neurobiol 69:203鈥?11CrossRef PubMed
  85.Cirillo G, Maggio N, Bianco MR, Vollono C, Sellitti S, Papa M (2010) Discriminative behavioral assessment unveils remarkable reactive astrocytosis and early molecular correlates in basal ganglia of 3-nitropropionic acid subchronic treated rats. Neurochem Int 56:152鈥?60CrossRef PubMed
  86.Giovannoni R, Maggio N, Bianco MR, Cavaliere C, Cirillo G, Lavitrano M, Papa M (2007) Reactive astrocytosis and glial glutamate transporter clustering are early changes in a spinocerebellar ataxia type 1 transgenic mouse model. Neuron Glia Biol 3:335鈥?51CrossRef PubMed
  87.Heneka MT, O鈥橞anion MK, Terwel D, Kummer MP (2010) Neuroinflammatory processes in Alzheimer鈥檚 disease. J Neural Transm 117:919鈥?47CrossRef PubMed
  88.Zagami CJ, Beart PM, Wallis N, Nagley P, O鈥橲hea RD (2009) Oxidative and excitotoxic insults exert differential effects on spinal motoneurons and astrocytic glutamate transporters: implications for the role of astrogliosis in amyotrophic lateral sclerosis. Glia 57:119鈥?35CrossRef PubMed
  
• 作者单位：Giovanni Cirillo (1)
  Anna Maria Colangelo (2) (3)
  Miluscia Berbenni (2) (3)
  Vita Maria Ippolito (2) (3)
  Ciro De Luca (1)
  Francesco Verdesca (1)
  Leonilde Savarese (1)
  Lilia Alberghina (2) (3)
  Nicola Maggio (4) (5)
  Michele Papa (1) (3)
  
  1. Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, Second University of Naples, via L. Armanni, 5, 80138, Naples, Italy
  2. Laboratory of Neuroscience 鈥淩. Levi-Montalcini鈥? Department of Biotechnology and Biosciences, University of Milano-Bicocca, Milan, Italy
  3. SYSBIO, Centre of Systems Biology, University of Milano-Bicocca, Milan, Italy
  4. Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, Tel HaShomer, Israel
  5. Department of Neurology and the J. Sagol Neuroscience Center, The Chaim Sheba Medical Center, Tel HaShomer, Israel
  
• 刊物主题：Neurosciences; Neurobiology; Cell Biology; Neurology;
• 出版者：Springer US
• ISSN：1559-1182

文摘

Modulation of spinal reactive gliosis following peripheral nerve injury (PNI) is a promising strategy to restore synaptic homeostasis. Oxidized ATP (OxATP), a nonselective antagonist of purinergic P2X receptors, was found to recover a neuropathic behavior following PNI. We investigated the role of intraperitoneal (i.p.) OxATP treatment in restoring the expression of neuronal and glial markers in the mouse spinal cord after sciatic spared nerve injury (SNI). Using in vivo two-photon microscopy, we imaged Ca2+ transients in neurons and astrocytes of the dorsal horn of spinal cord at rest and upon right hind paw electrical stimulation in sham, SNI, and OxATP-treated mice. Neuropathic behavior was investigated by von Frey and thermal plantar test. Glial [glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1)] and GABAergic [vesicular GABA transporter (vGAT) and glutamic acid decarboxylase 65/76 (GAD65/67)] markers and glial [glutamate transporter (GLT1) and GLAST] and neuronal amino acid [EAAC1, vesicular glutamate transporter 1 (vGLUT1)] transporters have been evaluated. In SNI mice, we found (i) increased glial response, (ii) decreased glial amino acid transporters, and (iii) increased levels of neuronal amino acid transporters, and (iv) in vivo analysis of spinal neurons and astrocytes showed a persistent increase of Ca2+ levels. OxATP administration reduced glial activation, modulated the expression of glial and neuronal glutamate/GABA transporters, restored neuronal and astrocytic Ca2+ levels, and prevented neuropathic behavior. In vitro studies validated that OxATP (i) reduced levels of reactive oxygen species (ROS), (ii) reduced astrocytic proliferation, (iii) increase vGLUT expression. All together, these data support the correlation between reactive gliosis and perturbation of the spinal synaptic homeostasis and the role played by the purinergic system in modulating spinal plasticity following PNI. Keywords Reactive astrocytosis Neuroglial network Calcium imaging Synaptic homeostasis Maladaptive plasticity Nerve injury