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Brain-derived neurotrophic factor from microglia: a molecular substrate for neuropathic pain

Published online by Cambridge University Press:  22 May 2012

Tuan Trang ,
Simon Beggs  and
Michael W. Salter
Tuan Trang
Affiliation:
Program in Neurosciences and Mental Health, Hospital for Sick Children, Department of Physiology, University of Toronto and the University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada
Simon Beggs
Affiliation:
Program in Neurosciences and Mental Health, Hospital for Sick Children, Department of Physiology, University of Toronto and the University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada
Michael W. Salter*
Affiliation:
Program in Neurosciences and Mental Health, Hospital for Sick Children, Department of Physiology, University of Toronto and the University of Toronto Centre for the Study of Pain, Toronto, Ontario, Canada
*
Correspondence should be addressed to: Michael W. Salter, Program in Neurosciences and Mental Health, Hospital for Sick Children, 555 University Avenue, Toronto, Ontario, M5G 1X8Canada email: mike.salter@utoronto.ca
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Abstract

One of the most significant advances in pain research is the realization that neurons are not the only cell type involved in the etiology of chronic pain. This realization has caused a radical shift from the previous dogma that neuronal dysfunction alone accounts for pain pathologies to the current framework of thinking that takes into account all cell types within the central nervous system (CNS). This shift in thinking stems from growing evidence that glia can modulate the function and directly shape the cellular architecture of nociceptive networks in the CNS. Microglia, in particular, are increasingly recognized as active principal players that respond to changes in physiological homeostasis by extending their processes toward the site of neural damage, and by releasing specific factors that have profound consequences on neuronal function and that contribute to CNS pathologies caused by disease or injury. A key molecule that modulates microglia activity is ATP, an endogenous ligand of the P2 receptor family. Microglia expresses several P2 receptor subtypes, and of these the P2X4 receptor subtype has emerged as a core microglia–neuron signaling pathway: activation of this receptor drives the release of brain-derived neurotrophic factor (BDNF), a cellular substrate that causes disinhibition of pain-transmitting spinal lamina I neurons. Converging evidence points to BDNF from spinal microglia as being a critical microglia–neuron signaling molecule that gates aberrant nociceptive processing in the spinal cord. The present review highlights recent advances in our understanding of P2X4 receptor-mediated signaling and regulation of BDNF in microglia, as well as the implications for microglia–neuron interactions in the pathobiology of neuropathic pain.

Keywords

Microgliabrain-derived neurotrophic factorpurinoceptorsneuropathic painnerve injurychronic pain

Information

Type
Reviews
Information
Neuron Glia Biology , Volume 7 , Special Issue 1: The Physiological Function of Microglia , February 2011 , pp. 99 - 108
Copyright
Copyright © Cambridge University Press 2012

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References

REFERENCES

Balkowiec, A. and Katz, D.M. (2002) Cellular mechanisms regulating activity-dependent release of native brain-derived neurotrophic factor from hippocampal neurons. Journal of Neuroscience 22, 10399–10407.CrossRefGoogle ScholarPubMed
Beggs, S. and Salter, M.W. (2010) Microglia-neuronal signalling in neuropathic pain hypersensitivity 2.0. Current Opinion in Neurobiology 20, 474–480.CrossRefGoogle ScholarPubMed
Bernier, L.P., Boue-Grabot, E. and Seguela, P. (2010) Functional modulation of P2X4 receptor-channels by UDP-activated P2Y6 receptors.Google Scholar
Bernier, L.P., Ase, A.R., Chevallier, S., Blais, D., Zhao, Q., Boue-Grabot, E. et al. (2008) Phosphoinositides regulate P2X4 ATP-gated channels through direct interactions. Journal of Neuroscience 28, 12938–12945.CrossRefGoogle ScholarPubMed
Biber, K., Tsuda, M., Tozaki-Saitoh, H., Tsukamoto, K., Toyomitsu, E., Masuda, T. et al. (2011) Neuronal CCL21 up-regulates microglia P2X4 expression and initiates neuropathic pain development. EMBO Journal.CrossRefGoogle ScholarPubMed
Biggs, J.E., Lu, V.B., Stebbing, M.J., Balasubramanyan, S. and Smith, P.A. (2010) Is BDNF sufficient for information transfer between microglia and dorsal horn neurons during the onset of central sensitization? Molecular Pain 6, 44.CrossRefGoogle ScholarPubMed
Blanquet, P.R. (2000) Identification of two persistently activated neurotrophin-regulated pathways in rat hippocampus. Neuroscience 95, 705–719.CrossRefGoogle ScholarPubMed
Bobanovic, L.K., Royle, S.J. and Murrell-Lagnado, R.D. (2002) P2X receptor trafficking in neurons is subunit specific. Journal of Neuroscience 22, 4814–4824.CrossRefGoogle ScholarPubMed
Boucsein, C., Zacharias, R., Farber, K., Pavlovic, S., Hanisch, U.K. and Kettenmann, H. (2003) Purinergic receptors on microglial cells: functional expression in acute brain slices and modulation of microglial activation in vitro. European Journal of Neuroscience 17, 2267–2276.CrossRefGoogle ScholarPubMed
Brone, B., Moechars, D., Marrannes, R., Mercken, M. and Meert, T. (2007) P2X currents in peritoneal macrophages of wild type and P2X4−/− mice. Immunology Letters 113, 83–89.CrossRefGoogle ScholarPubMed
Broom, D.C., Matson, D.J., Bradshaw, E., Buck, M.E., Meade, R., Coombs, S. et al. (2008) Characterization of N-(adamantan-1-ylmethyl)-5-[(3R-amino-pyrrolidin-1-yl)methyl]-2-chloro-ben zamide, a P2X7 antagonist in animal models of pain and inflammation. Journal of Pharmacology and Experimental Therapeutics 327, 620–633.CrossRefGoogle Scholar
Buldyrev, I., Tanner, N.M., Hsieh, H.Y., Dodd, E.G., Nguyen, L.T. and Balkowiec, A. (2006) Calcitonin gene-related peptide enhances release of native brain-derived neurotrophic factor from trigeminal ganglion neurons. Journal of Neurochemistry 99, 1338–1350.CrossRefGoogle ScholarPubMed
Burnstock, G. (2006a) Pathophysiology and therapeutic potential of purinergic signaling. Pharmacology Review 58, 58–86.CrossRefGoogle ScholarPubMed
Burnstock, G. (2006b) Purinergic P2 receptors as targets for novel analgesics. Pharmacology and Therapeutics 110, 433–454.CrossRefGoogle ScholarPubMed
Bushong, E.A., Martone, M.E., Jones, Y.Z. and Ellisman, M.H. (2002) Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. Journal of Neuroscience 22, 183–192.CrossRefGoogle ScholarPubMed
Calvo, M. and Bennett, D.L. (2011) The mechanisms of microgliosis and pain following peripheral nerve injury. Experimental NeurologyGoogle ScholarPubMed
Calvo, M., Zhu, N., Grist, J., Ma, Z., Loeb, J.A. and Bennett, D.L. (2011) Following nerve injury neuregulin-1 drives microglial proliferation and neuropathic pain via the MEK/ERK pathway. Glia 59, 554–568.CrossRefGoogle ScholarPubMed
Chen, W.G., Chang, Q., Lin, Y., Meissner, A., West, A.E., Griffith, E.C. et al. (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302, 885–889.CrossRefGoogle ScholarPubMed
Chessell, I.P., Hatcher, J.P., Bountra, C., Michel, A.D., Hughes, J.P., Green, P. et al. (2005) Disruption of the P2X7 purinoceptor gene abolishes chronic inflammatory and neuropathic pain. Pain 114, 386–396.CrossRefGoogle ScholarPubMed
Clark, A.K., Wodarski, R., Guida, F., Sasso, O. and Malcangio, M. (2010) Cathepsin S release from primary cultured microglia is regulated by the P2X7 receptor. Glia 58, 1710–1726.CrossRefGoogle ScholarPubMed
Clark, A.K., Yip, P.K., Grist, J., Gentry, C., Staniland, A.A., Marchand, F. et al. (2007) Inhibition of spinal microglial cathepsin S for the reversal of neuropathic pain. Proceedings of the National Academy of Sciences of the U.S.A. 104, 10655–10660.CrossRefGoogle ScholarPubMed
Collo, G., Neidhart, S., Kawashima, E., Kosco-Vilbois, M., North, R.A. and Buell, G. (1997) Tissue distribution of the P2X7 receptor. Neuropharmacology 36, 1277–1283.CrossRefGoogle ScholarPubMed
Costigan, M., Scholz, J. and Woolf, C.J. (2009) Neuropathic pain: a maladaptive response of the nervous system to damage. Annual Review of Neuroscience 32, 1–32.CrossRefGoogle ScholarPubMed
Coull, J.A., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K. et al. (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017–1021.CrossRefGoogle ScholarPubMed
Coull, J.A., Boudreau, D., Bachand, K., Prescott, S.A., Nault, F., Sik, A. et al. (2003) Trans-synaptic shift in anion gradient in spinal lamina I neurons as a mechanism of neuropathic pain. Nature 424, 938–942.CrossRefGoogle ScholarPubMed
Coyle, D.E. (1998) Partial peripheral nerve injury leads to activation of astroglia and microglia which parallels the development of allodynic behavior. Glia 23, 75–83.3.0.CO;2-3>CrossRefGoogle ScholarPubMed
Davalos, D., Grutzendler, J., Yang, G., Kim, J.V., Zuo, Y., Jung, S. et al. (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nature Neuroscience 8, 752–758.CrossRefGoogle ScholarPubMed
de Jong, E.K., Dijkstra, I.M., Hensens, M., Brouwer, N., van, A.M., Liem, R.S. et al. (2005) Vesicle-mediated transport and release of CCL21 in endangered neurons: a possible explanation for microglia activation remote from a primary lesion. Journal of Neuroscience 25, 7548–7557.CrossRefGoogle ScholarPubMed
De Koninck, Y. (2007) Altered chloride homeostasis in neurological disorders: a new target. Current Opinion in Pharmacology 7, 93–99.CrossRefGoogle ScholarPubMed
Dehez, S., Daulhac, L., Kowalski-Chauvel, A., Fourmy, D., Pradayrol, L. and Seva, C. (2001) Gastrin-induced DNA synthesis requires p38-MAPK activation via PKC/Ca(2+) and Src-dependent mechanisms. FEBS Letters 496, 25–30.CrossRefGoogle ScholarPubMed
Dell'Antonio, G., Quattrini, A., Cin, E.D., Fulgenzi, A. and Ferrero, M.E. (2002) Relief of inflammatory pain in rats by local use of the selective P2X7 ATP receptor inhibitor, oxidized ATP. Arthritis and Rheumatology 46, 3378–3385.CrossRefGoogle ScholarPubMed
Di, V.F. (2006) Purinergic signalling between axons and microglia. Novartis Foundation Symposia 276, 253–258.Google Scholar
Donnelly-Roberts, D.L. and Jarvis, M.F. (2007) Discovery of P2X7 receptor-selective antagonists offers new insights into P2X7 receptor function and indicates a role in chronic pain states. British Journal of Pharmacology 151, 571–579.CrossRefGoogle ScholarPubMed
Donnelly-Roberts, D., McGaraughty, S., Shieh, C.C., Honore, P. and Jarvis, M.F. (2008) Painful purinergic receptors. Journal of Pharmacology and Experimental Therapeutics 324, 409–415.CrossRefGoogle ScholarPubMed
Echeverry, S., Shi, X.Q. and Zhang, J. (2008) Characterization of cell proliferation in rat spinal cord following peripheral nerve injury and the relationship with neuropathic pain. Pain 135, 37–47.CrossRefGoogle ScholarPubMed
Farber, K. and Kettenmann, H. (2005) Physiology of microglial cells. Brain Research, Brain Research Reviews 48, 133–143.CrossRefGoogle ScholarPubMed
Ferrari, D., Villalba, M., Chiozzi, P., Falzoni, S., Ricciardi-Castagnoli, P. and Di, V.F. (1996) Mouse microglial cells express a plasma membrane pore gated by extracellular ATP. Journal of Immunology 156, 1531–1539.CrossRefGoogle ScholarPubMed
Fountain, S.J. and North, R.A. (2006) A C-terminal lysine that controls human P2X4 receptor desensitization. Journal of Biological Chemistry 281, 15044–15049.CrossRefGoogle ScholarPubMed
Fujii, K., Young, M.T. and Harris, K.D. (2011) Exploiting powder X-ray diffraction for direct structure determination in structural biology: the P2X4 receptor trafficking motif YEQGL. Journal of Structural Biology 174, 461–467.CrossRefGoogle ScholarPubMed
Ghosh, A., Carnahan, J. and Greenberg, M.E. (1994) Requirement for BDNF in activity-dependent survival of cortical neurons. Science 263, 1618–1623.CrossRefGoogle ScholarPubMed
Ginhoux, F., Greter, M., Leboeuf, M., Nandi, S., See, P., Gokhan, S. et al. (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330, 841–845.CrossRefGoogle ScholarPubMed
Grace, P.M., Rolan, P.E. and Hutchinson, M.R. (2011) Peripheral immune contributions to the maintenance of central glial activation underlying neuropathic pain. Brain, Behavior, and Immunity 25, 1322–1332.CrossRefGoogle Scholar
Graeber, M.B. (2010) Changing face of microglia. Science 330, 783–788.CrossRefGoogle ScholarPubMed
Gwak, Y.S. and Hulsebosch, C.E. (2009) Remote astrocytic and microglial activation modulates neuronal hyperexcitability and below-level neuropathic pain after spinal injury in rat. Neuroscience 161, 895–903.CrossRefGoogle ScholarPubMed
Gwak, Y.S. and Hulsebosch, C.E. (2010) ‘Gliopathy’ maintains persistent hyperexcitability of spinal dorsal horn neurons after spinal cord injury: substrate of central neuropathic pain. In Costa, A. and Villalba, E. (eds) Horizons in Neuroscience Research, Volume 1. Hauppauge, NY: Nova Science Publishers Inc., pp. 195–224.Google Scholar
Hanisch, U.K. and Kettenmann, H. (2007) Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nature Neuroscience 10, 1387–1394.CrossRefGoogle ScholarPubMed
Hepp, R., Perraut, M., Chasserot-Golaz, S., Galli, T., Aunis, D., Langley, K. et al. (1999) Cultured glial cells express the SNAP-25 analogue SNAP-23. Glia 27, 181–187.3.0.CO;2-9>CrossRefGoogle ScholarPubMed
Honore, P., Donnelly-Roberts, D., Namovic, M.T., Hsieh, G., Zhu, C.Z., Mikusa, J.P. et al. (2006) A-740003 [N-(1-{[(cyanoimino)(5-quinolinylamino) methyl]amino}-2,2-dimethylpropyl)-2-(3,4-dimethoxyphenyl)acetamide], a novel and selective P2X7 receptor antagonist, dose-dependently reduces neuropathic pain in the rat. Journal of Pharmacology and Experimental Therapeutics 319, 1376–1385.CrossRefGoogle ScholarPubMed
Honore, P., Donnelly-Roberts, D., Namovic, M., Zhong, C., Wade, C., Chandran, P. et al. (2009) The antihyperalgesic activity of a selective P2X7 receptor antagonist, A-839977, is lost in IL-1alphabeta knockout mice. Behavioral Brain Research 204, 77–81.CrossRefGoogle ScholarPubMed
Inoue, K. and Tsuda, M. (2006) The role of microglia and ATP receptors in a mechanism of neuropathic pain. Nippon Yakurigaku Zasshi 127, 14–17.CrossRefGoogle Scholar
IOM (Institute of Medicine) (2011) Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Education, and Research. Washington, DC: The National Academies Press.Google Scholar
Jarvis, M.F. (2010) The neural-glial purinergic receptor ensemble in chronic pain states. Trends in Neurosciences 33, 48–57.CrossRefGoogle ScholarPubMed
Ji, R.R. and Woolf, C.J. (2001) Neuronal plasticity and signal transduction in nociceptive neurons: implications for the initiation and maintenance of pathological pain. Neurobiology of Disease 8, 1–10.CrossRefGoogle ScholarPubMed
Jin, S.X., Zhuang, Z.Y., Woolf, C.J. and Ji, R.R. (2003) p38 mitogen-activated protein kinase is activated after a spinal nerve ligation in spinal cord microglia and dorsal root ganglion neurons and contributes to the generation of neuropathic pain. Journal of Neuroscience 23, 4017–4022.CrossRefGoogle Scholar
Kawate, T., Michel, J.C., Birdsong, W.T. and Gouaux, E. (2009) Crystal structure of the ATP-gated P2X(4) ion channel in the closed state. Nature 460, 592–598.CrossRefGoogle ScholarPubMed
Keller, A.F., Beggs, S., Salter, M.W. and De Koninck, Y. (2007) Transformation of the output of spinal lamina I neurons after nerve injury and microglia stimulation underlying neuropathic pain. Molecular Pain 3, 27.CrossRefGoogle ScholarPubMed
Kettenmann, H., Hanisch, U.K., Noda, M. and Verkhratsky, A. (2011) Physiology of microglia. Physiology Review 91, 461–553.CrossRefGoogle ScholarPubMed
Kobayashi, K., Yamanaka, H., Fukuoka, T., Dai, Y., Obata, K. and Noguchi, K. (2008) P2Y12 receptor upregulation in activated microglia is a gateway of p38 signaling and neuropathic pain. Journal of Neuroscience 28, 2892–2902.CrossRefGoogle ScholarPubMed
Kolarow, R., Brigadski, T. and Lessmann, V. (2007) Postsynaptic secretion of BDNF and NT-3 from hippocampal neurons depends on calcium calmodulin kinase II signaling and proceeds via delayed fusion pore opening. Journal of Neurosciences 27, 10350–10364.CrossRefGoogle ScholarPubMed
Kreutzberg, G.W. (1996) Microglia: a sensor for pathological events in the CNS. Trends in Neuroscience 19, 312–318.CrossRefGoogle ScholarPubMed
Latremoliere, A. and Woolf, C.J. (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. Journal of Pain 10, 895–926.CrossRefGoogle ScholarPubMed
Lauterborn, J.C., Rivera, S., Stinis, C.T., Hayes, V.Y., Isackson, P.J. and Gall, C.M. (1996) Differential effects of protein synthesis inhibition on the activity-dependent expression of BDNF transcripts: evidence for immediate-early gene responses from specific promoters. Journal of Neuroscience 16, 7428–7436.CrossRefGoogle ScholarPubMed
Lawson, L.J., Perry, V.H., Dri, P. and Gordon, S. (1990) Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain. Neuroscience 39, 151–170.CrossRefGoogle ScholarPubMed
Lever, I., Cunningham, J., Grist, J., Yip, P.K. and Malcangio, M. (2003) Release of BDNF and GABA in the dorsal horn of neuropathic rats. European Journal of Neuroscience 18, 1169–1174.CrossRefGoogle ScholarPubMed
Lipsky, R.H., Xu, K., Zhu, D., Kelly, C., Terhakopian, A., Novelli, A. et al. (2001) Nuclear factor kappaB is a critical determinant in N-methyl-d-aspartate receptor-mediated neuroprotection. Journal of Neurochemistry 78, 254–264.CrossRefGoogle ScholarPubMed
Liu, L., Tornqvist, E., Mattsson, P., Eriksson, N.P., Persson, J.K., Morgan, B.P. et al. (1995) Complement and clusterin in the spinal cord dorsal horn and gracile nucleus following sciatic nerve injury in the adult rat. Neuroscience 68, 167–179.CrossRefGoogle ScholarPubMed
Lu, V.B., Ballanyi, K., Colmers, W.F. and Smith, P.A. (2007) Neuron type-specific effects of brain-derived neurotrophic factor in rat superficial dorsal horn and their relevance to ‘central sensitization'. Journal of Physiology 584, 543–563.CrossRefGoogle ScholarPubMed
Maeda, M., Tsuda, M., Tozaki-Saitoh, H., Inoue, K. and Kiyama, H. (2010) Nerve injury-activated microglia engulf myelinated axons in a P2Y12 signaling-dependent manner in the dorsal horn. Glia 58, 1838–1846.CrossRefGoogle Scholar
Marini, A.M., Jiang, X., Wu, X., Tian, F., Zhu, D., Okagaki, P. et al. (2004) Role of brain-derived neurotrophic factor and NF-kappaB in neuronal plasticity and survival: from genes to phenotype. Restorative Neurology and Neuroscience 22, 121–130.Google ScholarPubMed
McGaraughty, S., Chu, K.L., Namovic, M.T., Donnelly-Roberts, D.L., Harris, R.R., Zhang, X.F. et al. (2007) P2X7-related modulation of pathological nociception in rats. Neuroscience 146, 1817–1828.CrossRefGoogle ScholarPubMed
Milligan, E.D. and Watkins, L.R. (2009) Pathological and protective roles of glia in chronic pain. Nature Reviews Neuroscience 10, 23–36.CrossRefGoogle ScholarPubMed
Nakajima, K. and Kohsaka, S. (2001) Microglia: activation and their significance in the central nervous system. Journal of Biochemistry (Tokyo) 130, 169–175.CrossRefGoogle ScholarPubMed
Nasu-Tada, K., Koizumi, S., Tsuda, M., Kunifusa, E. and Inoue, K. (2006) Possible involvement of increase in spinal fibronectin following peripheral nerve injury in upregulation of microglial P2X4, a key molecule for mechanical allodynia. Glia 53, 769–775.CrossRefGoogle ScholarPubMed
Nimmerjahn, A., Kirchhoff, F. and Helmchen, F. (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308, 1314–1318.CrossRefGoogle ScholarPubMed
North, R.A. (2002) Molecular physiology of P2X receptors. Physiological Review 82, 1013–1067.CrossRefGoogle ScholarPubMed
Obata, K., Yamanaka, H., Dai, Y., Mizushima, T., Fukuoka, T., Tokunaga, A. et al. (2004) Differential activation of MAPK in injured and uninjured DRG neurons following chronic constriction injury of the sciatic nerve in rats. European Journal of Neuroscience 20, 2881–2895.CrossRefGoogle ScholarPubMed
Obata, N., Mizobuchi, S., Itano, Y., Matsuoka, Y., Kaku, R., Tomotsuka, N. et al. (2011) Decoy strategy targeting the brain-derived neurotrophic factor exon I to attenuate tactile allodynia in the neuropathic pain model of rats. Biochemical and Biophysical Research Communications 408, 139–144.CrossRefGoogle ScholarPubMed
Perez-Medrano, A., Donnelly-Roberts, D.L., Honore, P., Hsieh, G.C., Namovic, M.T., Peddi, S. et al. (2009) Discovery and biological evaluation of novel cyanoguanidine P2X(7) antagonists with analgesic activity in a rat model of neuropathic pain. Journal of Medicinal Chemistry 52, 3366–3376.CrossRefGoogle Scholar
Portanova, J.P., Zhang, Y., Anderson, G.D., Hauser, S.D., Masferrer, J.L., Seibert, K. et al. (1996) Selective neutralization of prostaglandin E2 blocks inflammation, hyperalgesia, and interleukin 6 production in vivo. Journal of Experimental Medicine 184, 883–891.CrossRefGoogle ScholarPubMed
Qureshi, O.S., Paramasivam, A., Yu, J.C. and Murrell-Lagnado, R.D. (2007) Regulation of P2X4 receptors by lysosomal targeting, glycan protection and exocytosis. Journal of Cell Science 120, 3838–3849.CrossRefGoogle ScholarPubMed
Rao, J.S., Ertley, R.N., Lee, H.J., DeMar, J.C. Jr., Arnold, J.T., Rapoport, S.I. et al. (2007) n-3 polyunsaturated fatty acid deprivation in rats decreases frontal cortex BDNF via a p38 MAPK-dependent mechanism. Molecular Psychiatry 12, 36–46.CrossRefGoogle Scholar
Rivest, S. (2009) Regulation of innate immune responses in the brain. Nature Reviews Immunology 9, 429–439.CrossRefGoogle ScholarPubMed
Royle, S.J., Bobanovic, L.K. and Murrell-Lagnado, R.D. (2002) Identification of a non-canonical tyrosine-based endocytic motif in an ionotropic receptor. Journal of Biological Chemistry 277, 35378–35385.CrossRefGoogle Scholar
Samad, T.A., Sapirstein, A. and Woolf, C.J. (2002) Prostanoids and pain: unraveling mechanisms and revealing therapeutic targets. Trends in Molecular Medicine 8, 390–396.CrossRefGoogle ScholarPubMed
Sasaki, Y., Hoshi, M., Akazawa, C., Nakamura, Y., Tsuzuki, H., Inoue, K. et al. (2003) Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia 44, 242–250.CrossRefGoogle ScholarPubMed
Scholz, J. and Woolf, C.J. (2002) Can we conquer pain? Nature Neuroscience 5 (Suppl.), 1062–1067.CrossRefGoogle ScholarPubMed
Seil, M., El, O.M., Fontanils, U., Etxebarria, I.G., Pochet, S., Dal, M.G. et al. (2010) Ivermectin-dependent release of IL-1beta in response to ATP by peritoneal macrophages from P2X(7)-KO mice. Purinergic Signalling 6, 405–416.CrossRefGoogle ScholarPubMed
Shinozaki, Y., Sumitomo, K., Tsuda, M., Koizumi, S., Inoue, K. and Torimitsu, K. (2009) Direct Observation of ATP-induced conformational changes in single P2X4 receptors. PLoS Biology 7, e103.CrossRefGoogle Scholar
Skaper, S.D., Debetto, P. and Giusti, P. (2010) The P2X7 purinergic receptor: from physiology to neurological disorders. FASEB Journal 24, 337–345.CrossRefGoogle ScholarPubMed
Sorge, R.E., Trang, T., Dorfman, R., Smith, S.B., Beggs, S., Ritchie, J. et al. (2012) Genetically determined P2X7 receptor pore formation regulates variability in chronic pain sensitivity. Native Medicine 18, 595–599.CrossRefGoogle ScholarPubMed
Sweitzer, S.M., White, K.A., Dutta, C. and DeLeo, J.A. (2002) The differential role of spinal MHC class II and cellular adhesion molecules in peripheral inflammatory versus neuropathic pain in rodents. Journal of Neuroimmunology 125, 82–93.CrossRefGoogle ScholarPubMed
Tanga, F.Y., Raghavendra, V. and DeLeo, J.A. (2004) Quantitative real-time RT-PCR assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochemistry International 45, 397–407.CrossRefGoogle Scholar
Tao, X., Finkbeiner, S., Arnold, D.B., Shaywitz, A.J. and Greenberg, M.E. (1998) Ca2+ influx regulates BDNF transcription by a CREB family transcription factor-dependent mechanism. Neuron 20, 709–726.CrossRefGoogle ScholarPubMed
Toulme, E., Soto, F., Garret, M. and Boue-Grabot, E. (2006) Functional properties of internalization-deficient P2X4 receptors reveal a novel mechanism of ligand-gated channel facilitation by ivermectin. Molecular Pharmacology 69, 576–587.CrossRefGoogle ScholarPubMed
Toyomitsu, E., Tsuda, M., Yamashita, T., Tozaki-Saitoh, H., Tanaka, Y. and Inoue, K. (2012) CCL2 promotes P2X4 receptor trafficking to the cell surface of microglia. Purinergic Signalling 2012 Jan 6 [Epub ahead of print].CrossRefGoogle Scholar
Tozaki-Saitoh, H., Tsuda, M., Miyata, H., Ueda, K., Kohsaka, S. and Inoue, K. (2008) P2Y12 receptors in spinal microglia are required for neuropathic pain after peripheral nerve injury. Journal of Neuroscience 28, 4949–4956.CrossRefGoogle ScholarPubMed
Trang, T., Beggs, S. and Salter, M.W. (2006) Purinoceptors in microglia and neuropathic pain. Pflugers Archives 452, 645–652.CrossRefGoogle ScholarPubMed
Trang, T., Beggs, S. and Salter, M.W. (2011) ATP receptors gate microglia signaling in neuropathic pain. Experimental Neurology 234, 354–361.CrossRefGoogle ScholarPubMed
Trang, T., Beggs, S., Wan, X. and Salter, M.W. (2009) P2X4-receptor-mediated synthesis and release of brain-derived neurotrophic factor in microglia is dependent on calcium and p38-mitogen-activated protein kinase activation. Journal of Neuroscience 29, 3518–3528.CrossRefGoogle ScholarPubMed
Tsuda, M., Inoue, K. and Salter, M.W. (2005) Neuropathic pain and spinal microglia: a big problem from molecules in “small” glia. Trends in Neurosciences 28, 101–107.CrossRefGoogle ScholarPubMed
Tsuda, M., Mizokoshi, A., Shigemoto-Mogami, Y., Koizumi, S. and Inoue, K. (2004) Activation of p38 mitogen-activated protein kinase in spinal hyperactive microglia contributes to pain hypersensitivity following peripheral nerve injury. Glia 45, 89–95.CrossRefGoogle ScholarPubMed
Tsuda, M., Shigemoto-Mogami, Y., Koizumi, S., Mizokoshi, A., Kohsaka, S., Salter, M.W. et al. (2003) P2X4 receptors induced in spinal microglia gate tactile allodynia after nerve injury. Nature 424, 778–783.CrossRefGoogle ScholarPubMed
Tsuda, M., Toyomitsu, E., Komatsu, T., Masuda, T., Kunifusa, E., Nasu-Tada, K. et al. (2008a) Fibronectin/integrin system is involved in P2X(4) receptor upregulation in the spinal cord and neuropathic pain after nerve injury. Glia 56, 579–585.CrossRefGoogle ScholarPubMed
Tsuda, M., Tozaki-Saitoh, H., Masuda, T., Toyomitsu, E., Tezuka, T., Yamamoto, T. et al. (2008b) Lyn tyrosine kinase is required for P2X(4) receptor upregulation and neuropathic pain after peripheral nerve injury. Glia 56, 50–58.CrossRefGoogle ScholarPubMed
Tsuda, M., Kuboyama, K., Inoue, T., Nagata, K., Tozaki-Saitoh, H. and Inoue, K. (2009a) Behavioral phenotypes of mice lacking purinergic P2X4 receptors in acute and chronic pain assays. Molecular Pain 5, 28.CrossRefGoogle ScholarPubMed
Tsuda, M., Masuda, T., Kitano, J., Shimoyama, H., Tozaki-Saitoh, H. and Inoue, K. (2009b) IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proceedings of the National Academy of Sciences of the U.S.A. 106, 8032–8037.CrossRefGoogle ScholarPubMed
Tsuda, M., Toyomitsu, E., Kometani, M., Tozaki-Saitoh, H. and Inoue, K. (2009c) Mechanisms underlying fibronectin-induced up-regulation of P2X4R expression in microglia: distinct roles of PI3 K-Akt and MEK-ERK signalling pathways. Journal of Cellular and Molecular Medicine 13, 3251–3259.CrossRefGoogle Scholar
Ulmann, L., Hatcher, J.P., Hughes, J.P., Chaumont, S., Green, P.J., Conquet, F. et al. (2008) Up-regulation of P2X4 receptors in spinal microglia after peripheral nerve injury mediates BDNF release and neuropathic pain. Journal of Neuroscience 28, 11263–11268.CrossRefGoogle ScholarPubMed
Ulmann, L., Hirbec, H. and Rassendren, F. (2010) P2X4 receptors mediate PGE2 release by tissue-resident macrophages and initiate inflammatory pain. EMBO Journal 29, 2290–2300.CrossRefGoogle ScholarPubMed
Voscopoulos, C. and Lema, M. (2010) When does acute pain become chronic? British Journal of Anaesthesia 105 (Suppl. 1), i69–i85.CrossRefGoogle ScholarPubMed
Watkins, L.R. and Maier, S.F. (2003) Glia: a novel drug discovery target for clinical pain. Nature Reviews Drug Discovery 2, 973–985.CrossRefGoogle Scholar
Watkins, L.R., Milligan, E.D. and Maier, S.F. (2001) Glial activation: a driving force for pathological pain. Trends in Neurosciences 24, 450–455.CrossRefGoogle ScholarPubMed
West, A.E., Chen, W.G., Dalva, M.B., Dolmetsch, R.E., Kornhauser, J.M., Shaywitz, A.J. et al. (2001) Calcium regulation of neuronal gene expression. Proceedings of the National Academy of Sciences of the U.S.A. 98, 11024–11031.CrossRefGoogle ScholarPubMed
Woolf, C.J. and Salter, M.W. (2000) Neuronal plasticity: increasing the gain in pain. Science 288, 1765–1769.CrossRefGoogle ScholarPubMed
Yuan, H., Zhu, X., Zhou, S., Chen, Q., Zhu, X., Ma, X. et al. (2010) Role of mast cell activation in inducing microglial cells to release neurotrophin. Journal of Neuroscience Research 88, 1348–1354.CrossRefGoogle ScholarPubMed
Zhang, J. and De Koninck, Y. (2006) Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. Journal of Neurochemistry 97, 772–783.CrossRefGoogle ScholarPubMed
Zhao, J., Seereeram, A., Nassar, M.A., Levato, A., Pezet, S., Hathaway, G. et al. (2006) Nociceptor-derived brain-derived neurotrophic factor regulates acute and inflammatory but not neuropathic pain. Molecular and Cellular Neuroscience 31, 539–548.CrossRefGoogle Scholar
Zhou, Z., Hong, E.J., Cohen, S., Zhao, W.N., Ho, H.Y., Schmidt, L. et al. (2006) Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269.CrossRefGoogle ScholarPubMed
Zimmermann, M. (2001) Pathobiology of neuropathic pain. European Journal of Pharmacology 429, 23–37.CrossRefGoogle ScholarPubMed