Spinal astrocytes in pain processing: Non-neuronal cells as therapeutic targets

Molecular Interventions

Volumn 10, Issue 1, 2010, Pages 25-38

  Svensson, Camilla I ^a   Brodin, Ernst ^a  

^a KAROLINSKA INSTITUTE   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

ADENOSINE TRIPHOSPHATE; ANALGESIC AGENT; CALCITONIN GENE RELATED PEPTIDE; CHEMOKINE RECEPTOR CCR2; CHEMOKINE RECEPTOR CX3CR1; EXCITATORY AMINO ACID TRANSPORTER 1; EXCITATORY AMINO ACID TRANSPORTER 2; FRACTALKINE; GLIAL FIBRILLARY ACIDIC PROTEIN; GLUTAMIC ACID; INTERLEUKIN 1BETA; INTERLEUKIN 6; MONOCYTE CHEMOTACTIC PROTEIN 1; NEUROTRANSMITTER; PROSTAGLANDIN DERIVATIVE; PROTEIN S100B; SUBSTANCE P; THROMBOSPONDIN; TRANSFORMING GROWTH FACTOR; TUMOR NECROSIS FACTOR ALPHA; VESICULAR GLUTAMATE TRANSPORTER 1;

ARTHRITIS; ASTROCYTE; CELL ACTIVATION; CELL COMMUNICATION; CELL FUNCTION; CHRONIC INFLAMMATION; CHRONIC PAIN; GLIA CELL; HUMAN; HYPERALGESIA; MEDICAL RESEARCH; MICROGLIA; NERVE CELL; NERVE FIBER; NEUROMODULATION; NEUROPATHIC PAIN; NEUROTRANSMISSION; NOCICEPTION; NONHUMAN; PATHOGENESIS; PROTEIN EXPRESSION; REVIEW; SIGNAL TRANSDUCTION; SPINAL CORD; SPINAL CORD DORSAL HORN; SYNAPTIC TRANSMISSION;

ASTROCYTES; CHRONIC DISEASE; HUMANS; MICROGLIA; MODELS, BIOLOGICAL; NEURONS; PAIN; SPINE;

EID: 76349102800     PISSN: 15340384     EISSN: 15432548     Source Type: Journal    
DOI: 10.1124/mi.10.1.6     Document Type: Review

References (156)

1. Sherrington, C. Flexion-reflex of the limb, crossed extensionreflex and reflex stepping and standing. J. Physiol. (Lond) 28-121 (1910).
2. Willis, W.D., Jr. The role of trpv1 receptors in pain evoked by noxious thermal and chemical stimuli. Exp. Brain Res. 196, 5-11 (2009).
3. Campbell, J.N. and Meyer, R.A. Mechanisms of neuropathic pain. Neuron 52, 77-92 (2006).
4. Latremoliere, A. and Woolf, C.J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J. Pain 10, 895-926 (2009). An excellent review of central changes implicated in creation and maintenance of exaggerated pain states.
5. Ikeda, H., Kiritoshi, T., and Murase, K. Synaptic plasticity in the spinal dorsal horn. Neurosci. Res. 64, 133-136 (2009). 6. Yaksh, T.L. Central pharmacology of nociceptive transmission. Elsevier, Churchill Livingstone (2006).
6. Ren, K. and Dubner, R. Pain facilitation and activity-dependent plasticity in pain modulatory circuitry: Role of BDNF-TrkB signaling and NMDA receptors. Mol. Biol. Neurobiol. 35, 224-235 (2007).
7. Coull, J.A., Beggs, S., Boudreau, D., Boivin, D., Tsuda, M., Inoue, K., Gravel, C., Salter, M.W., and De Koninck, Y. BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438, 1017-1021 (2005).
8. Merighi, A., Salio, C., Ghirri, A., Lossi, L., Ferrini, F., Betelli, C., and Bardoni, R. BDNF as a pain modulator. Prog. Biol. Neurobiol. 85, 297-317 (2008).
9. Lu, V. B., Biggs, J. E., Stebbing, M.J. et al. Brain-derived neurotrophic factor drives the changes in excitatory synaptic transmission in the rat superficial dorsal horn that follow sciatic nerve injury. J. Physiol. 587, 1013-1032 (2009).
10. Garrison, C.J., Dougherty, P.M., Kajander, K.C., and Carlton, S.M. Staining of glial fibrillary acidic protein (GFAP) in lumbar spinal cord increases following a sciatic nerve constriction injury. Brain Res. 565, 1-7 (1991). This research article is historically important as it provides the first evidence that nerve damage, which creates neuropathic pain, also activates spinal cord astrocytes.
11. McMahon, S. B. and Malcangio, M. Current challenges in glia-pain biology. Neuron 64, 46-54 (2009). A recent review critically examining current evidence of central glia participating in the regulation of pain processing. The authors identify where critical knowledge is missing or remains uncertain.
12. Somjen, G.G. Electrophysiology of neuroglia. Annu. Rev. Physiol. 37, 163-190 (1975).
13. Araque, A., Carmignoto, G., and Haydon, P.G. Dynamic signaling between astrocytes and neurons. Annu. Rev. Physiol. 63, 795-813 (2001).
14. Galambos, R. Reflections on the conceptual origins of neuron-glia interactions. Neuron Glia Biol. 3, 89-91 (2007).
15. Haydon, P.G. and Carmignoto, G. Astrocyte control of synaptic transmission and neurovascular coupling. Physiol. Rev. 86, 1009-1031 (2006).
16. Raivich, G. Like cops on the beat: The active role of resting microglia. Trends Neurosci. 28, 571-573 (2005).
17. Scholz, J. and Woolf, C. J. The neuropathic pain triad: Neurons, immune cells and glia. Nat. Neurosci. 10, 1361-1368 (2007).
18. De Leo, J. A., Tawfik, V. L., and LaCroix-Fralish, M. L. The tetrapartite synapse: Path to CNS sensitization and chronic pain. Pain 122, 17-21 (2006). Synapses may no longer be considered to comprise only a pre-synaptic and a post-synaptic neuron. This review summarizes the evidence for a tetrapartite synapse, which includes an astrocyte, a microglial cell, and pre- and post-synaptic neuronal terminals, forming a functional unit that is critical for the generation and maintenance of pain.
19. Gee J. R. and Keller, J.N. Astrocytes: Regulation of brain homeostasis via apolipoprotein E. Int. J. Biochem. Cell Biol. 37, 1145-1150 (2005).
20. Ren, K. and Dubner, R. Neuron-glia crosstalk gets serious: Role in pain hypersensitivity. Curr. Opin. Anaesthesiol. 21, 570-579 (2008).
21. Seth, P. and Koul, N. Astrocyte, the star avatar: Redefined. J. Biosci. 33, 405-421 (2008).
22. Wang, D.D. and Bordey, A. The astrocyte odyssey. Prog. Biol. Neurobiol. 86, 342-367 (2008). An excellent review describing the characteristics that classify a cell as an astrocyte and the emerging functions of astrocytes in neuronal activity under physiological conditions.
23. Bushong, E.A., Martone, M.E., Jones, Y.Z., and Ellisman, M.H. Protoplasmic astrocytes in CA1 stratum radiatum occupy separate anatomical domains. J. Neurosci. 22, 183-192 (2002).
24. Halassa, M.M., Fellin, T., Takano, H., Dong, J.H., and Haydon, P.G. Synaptic islands defined by the territory of a single astrocyte. J. Neurosci. 27, 6473-6477 (2007).
25. Eng, L.F. Glial fibrillary acidic protein (GFAP): The major protein of glial intermediate filaments in differentiated astrocytes. J. Neuroimmunol. 8, 203-214 (1985).
26. Rothstein, J.D., Martin, L., Levey, A.I., Dykes-Hoberg, M., Jin, L., Wu, D., Nash, N., and Kuncl, R.W. Localization of neuronal and glial glutamate transporters. Neuron 13, 713-725 (1994).
27. Danbolt, N.C., Lehre, K.P., Dehnes, Y., Chaudhry, F.A., and Levy, L.M. Localization of transporters using transporter-specific antibodies. Methods Enzymol. 296, 388-407 (1998).
28. Raponi, E., Agenes, F., Delphin, C., Assard, N., Baudier, J., Legraverend, C., and Deloulme, J.C. S100B expression defines a state in which GFAP-expressing cells lose their neural stem cell potential and acquire a more mature developmental stage. Glia 55, 165-177 (2007).
29. Deloulme, J.C., Raponi, E., Gentil, B.J., Bertacchi, N., Marks, A., Labourdette, G., and Baudier, J. Nuclear expression of S100B in oligodendrocyte progenitor cells correlates with differentiation toward the oligodendroglial lineage and modulates oligodendrocytes maturation. Mol. Cell Neurosci. 27, 453-465 (2004).
30. Hachem, S., Aguirre, A., Vives, V., Marks, A., Gallo, V., and Legraverend, C. Spatial and temporal expression of S100B in cells of oligodendrocyte lineage. Glia 51, 81-97 (2005).
31. Wallraff A., Odermatt, B., Willecke, K., and Steinhauser, C. Distinct types of astroglial cells in the hippocampus differ in gap junction coupling. Glia 48, 36-43 48 (2004).
32. Hochstim C., Deneen, B., Lukaszewicz, A., Zhou, Q., and Anderson, D. J. Identification of positionally distinct astrocyte subtypes whose identities are specified by a homeodomain code. Cell 133, 510-522 133 (2008).
33. Sweitzer S. M., Colburn, R. W., Rutkowski, M., and DeLeo, J. A. Acute peripheral inflammation induces moderate glial activation and spinal il-1beta expression that correlates with pain behavior in the rat. Brain Res 829, 209-221 829 (1999).
34. Colburn R. W., and DeLeo, J. A. The effect of perineural colchicine on nerve injury-induced spinal glial activation and neuropathic pain behavior. Brain Res Bull 49, 419-427 49 (1999).
35. Gordh T., and Sharma, H. S. Chronic spinal nerve ligation induces microvascular permeability disturbances, astrocytic reaction, and structural changes in the rat spinal cord. Acta Neurochir Suppl 96, 335-340 96 (2006).
36. Ma W., and Quirion, R. Partial sciatic nerve ligation induces increase in the phosphorylation of extracellular signal-regulated kinase (erk) and c-jun n-terminal kinase (jnk) in astrocytes in the lumbar spinal dorsal horn and the gracile nucleus. Pain 99, 175-184 99 (2002).
37. Wang W., Wang, W., Mei, X., Huang, J., Wei, Y., Wang, Y., Wu, S., and Li, Y. Crosstalk between spinal astrocytes and neurons in nerve injury-induced neuropathic pain. PLoS One 4, e6973 4 (2009).
38. Zhuang Z. Y., Wen, Y. R., Zhang, D. R., Borsello, T., Bonny, C., Strichartz, G. R., Decosterd, I., and Ji, R. R. A peptide c-jun n-terminal kinase (jnk) inhibitor blocks mechanical allodynia after spinal nerve ligation: Respective roles of jnk activation in primary sensory neurons and spinal astrocytes for neuropathic pain development and maintenance. J Neurosci 26, 3551-3560 26 (2006). A well-designed study demonstrating that intracellular signaling pathways are activated in spinal astrocytes after spinal nerve ligation, and that blocking this flux, or astrocyte activation in general, attenuates neuropathic pain.
39. Obata H., Eisenach, J. C., Hussain, H., Bynum, T., and Vincler, M. Spinal glial activation contributes to postoperative mechanical hypersensitivity in the rat. J Pain 7, 816-822 7 (2006).
40. Honore P., Rogers, S. D., Schwei, M. J., Salak-Johnson, J. L., Luger, N. M., Sabino, M. C., Clohisy, D. R., and Mantyh, P. W. Murine models of inflammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 98, 585-598 98 (2000).
41. Zhang R. X., Liu, B., Wang, L., Ren, K., Qiao, J. T., Berman, B. M., and Lao, L. Spinal glial activation in a new rat model of bone cancer pain produced by prostate cancer cell inoculation of the tibia. Pain 118, 125-136 118 (2005).
42. Sweitzer S. M., Pahl, J. L., and DeLeo, J. A. Propentofylline attenuates vincristine-induced peripheral neuropathy in the rat. Neurosci Lett 400, 258-261 400 (2006).
43. Gwak Y. S., Crown, E. D., Unabia, G. C., and Hulsebosch, C. E. Propentofylline attenuates allodynia, glial activation and modulates gabaergic tone after spinal cord injury in the rat. Pain 138, 410-422 138 (2008).
44. Hulsebosch C. E. Gliopathy ensures persistent inflammation and chronic pain after spinal cord injury. Exp Neurol (2008).
45. Kawasaki Y., Xu, Z. Z., Wang, X., Park, J. Y., Zhuang, Z. Y., Tan, P. H., Gao, Y. J., Roy, K., Corfas, G., Lo, E. H., and Ji, R. R. Distinct roles of matrix metalloproteases in the early- and late-phase development of neuropathic pain. Nat Med 14, 331-336 14 (2008).
46. Hashizume H., DeLeo, J. A., Colburn, R. W., and Weinstein, J. N. Spinal glial activation and cytokine expression after lumbar root injury in the rat. Spine (Phila Pa 1976) 25, 1206-1217 25 (2000).
47. Tanga F. Y., Raghavendra, V., and DeLeo, J. A. Quantitative real-time rtpcr assessment of spinal microglial and astrocytic activation markers in a rat model of neuropathic pain. Neurochem Int 45, 397-407 45 (2004).
48. Guo W., Wang, H., Watanabe, M., Shimizu, K., Zou, S., LaGraize, S. C., Wei, F., Dubner, R., and Ren, K. Glial-cytokine-neuronal interactions underlying the mechanisms of persistent pain. J Neurosci 27, 6006-6018 27 (2007). A carefully conducted study examining the interaction between neurons and astrocytes in a trigeminal model of inflammatory pain. The paper provides support that astrocyte activation depends on neuronal input and that NMDA-receptor phosphorylation, SP, NO, and IL-1 are important for astrocyte activation.
49. Hald A., Nedergaard, S., Hansen, R. R., Ding, M., and Heegaard, A. M. Differential activation of spinal cord glial cells in murine models of neuropathic and cancer pain. Eur J Pain 13, 138-145 13 (2009).
50. Zhang J., and De Koninck, Y. Spatial and temporal relationship between monocyte chemoattractant protein-1 expression and spinal glial activation following peripheral nerve injury. J Neurochem 97, 772-783 97 (2006).
51. Tawfik V. L., Lacroix-Fralish, M. L., Bercury, K. K., Nutile-McMenemy, N., Harris, B. T., and Deleo, J. A. Induction of astrocyte differentiation by propentofylline increases glutamate transporter expression in vitro: Heterogeneity of the quiescent phenotype. Glia 54, 193-203 54 (2006). This research article provides the first evidence that reactive astrocytes display decreased expression of glutamate transporters, such as GLT-1, and that propentofylline, a "glia inhibitor" with anti-allodynic effect, causes a potent dose-dependent increase of GLT-1 expression.
52. Milligan E. D., Mehmert, K. K., Hinde, J. L., Harvey, L. O., Martin, D., Tracey, K. J., Maier, S. F., and Watkins, L. R. Thermal hyperalgesia and mechanical allodynia produced by intrathecal administration of the human immunodeficiency virus-1 (hiv-1) envelope glycoprotein, gp120. Brain Res 861, 105-116 861 (2000).
53. Sweitzer S. M., Schubert, P., and DeLeo, J. A. Propentofylline, a glial modulating agent, exhibits antiallodynic properties in a rat model of neuropathic pain. J Pharmacol Exp Ther 297, 1210-1217 297 (2001).
54. Tawfik V. L., Regan, M. R., Haenggeli, C., Lacroix-Fralish, M. L., Nutile-McMenemy, N., Perez, N., Rothstein, J. D., and DeLeo, J. A. Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience 152, 1086-1092 152 (2008).
55. Sun S., Cao, H., Han, M., Li, T. T., Zhao, Z. Q., and Zhang, Y. Q. Evidence for suppression of electroacupuncture on spinal glial activation and behavioral hypersensitivity in a rat model of monoarthritis. Brain Res Bull 75, 83-93 75 (2008).
56. Zhang T., Zhang, J., Shi, J., Feng, Y., Sun, Z. S., and Li, H. Antinociceptive synergistic effect of spinal mglur2/3 antagonist and glial cells inhibitor on peripheral inflammation-induced mechanical hypersensitivity. Brain Res Bull 79, 219-223 79 (2009).
57. Clark A. K., Gentry, C., Bradbury, E. J., McMahon, S. B., and Malcangio, M. Role of spinal microglia in rat models of peripheral nerve injury and inflammation. Eur J Pain (2006).
58. Kim D. S., Figueroa, K. W., Li, K. W., Boroujerdi, A., Yolo, T., and David Luo, Z. Profiling of dynamically changed gene expression in dorsal root ganglia post peripheral nerve injury and a critical role of injury-induced glial fibrillary acidic protein in maintenance of pain behaviors [corrected]. Pain 143, 114-122 143 (2009).
59. Eng L. F., Ghirnikar, R. S., and Lee, Y. L. Glial fibrillary acidic protein: Gfap-thirty-one years (1969-2000). Neurochem Res 25, 1439-1451 25 (2000).
60. McCall M. A., Gregg, R. G., Behringer, R. R., Brenner, M., Delaney, C. L., Galbreath, E. J., Zhang, C. L., Pearce, R. A., Chiu, S. Y., and Messing, A. Targeted deletion in astrocyte intermediate filament (gfap) alters neuronal physiology. Proc Natl Acad Sci U S A 93, 6361-6366 93 (1996).
61. Shibuki K., Gomi, H., Chen, L., Bao, S., Kim, J. J., Wakatsuki, H., Fujisaki, T., Fujimoto, K., Katoh, A., Ikeda, T., Chen, C., Thompson, R. F., and Itohara, S. Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in gfap mutant mice. Neuron 16, 587-599 16 (1996).
62. Tanaka H., Katoh, A., Oguro, K., Shimazaki, K., Gomi, H., Itohara, S., Masuzawa, T., and Kawai, N. Disturbance of hippocampal long-term potentiation after transient ischemia in gfap deficient mice. J Neurosci Res 67, 11-20 67 (2002).
63. Ji R. R., Gereau, R. W. t., Malcangio, M., and Strichartz, G. R. Map kinase and pain. Brain Res Rev 60, 135-148 60 (2009).
64. Katsura H., Obata, K., Miyoshi, K., Kondo, T., Yamanaka, H., Kobayashi, K., Dai, Y., Fukuoka, T., Sakagami, M., and Noguchi, K. Transforming growth factor-activated kinase 1 induced in spinal astrocytes contributes to mechanical hypersensitivity after nerve injury. Glia 56, 723-733 56 (2008).
65. Borsello T., Clarke, P. G., Hirt, L., Vercelli, A., Repici, M., Schorderet, D. F., Bogousslavsky, J., and Bonny, C. A peptide inhibitor of c-jun n-terminal kinase protects against excitotoxicity and cerebral ischemia. Nat Med 9, 1180-1186 9 (2003).
66. Gao Y. J., Zhang, L., Samad, O. A., Suter, M. R., Yasuhiko, K., Xu, Z. Z., Park, J. Y., Lind, A. L., Ma, Q., and Ji, R. R. Jnk-induced mcp-1 production in spinal cord astrocytes contributes to central sensitization and neuropathic pain. J Neurosci 29, 4096-4108 29 (2009).
67. Ji R. R., Kawasaki, Y., Zhuang, Z. Y., Wen, Y. R., and Decosterd, I. Possible role of spinal astrocytes in maintaining chronic pain sensitization: Review of current evidence with focus on bfgf/jnk pathway. Neuron Glia Biol 2, 259-269 2 (2006).
68. Daulhac L., Mallet, C., Courteix, C., Etienne, M., Duroux, E., Privat, A. M., Eschalier, A., and Fialip, J. Diabetes-induced mechanical hyperalgesia involves spinal mitogen-activated protein kinase activation in neurons and microglia via n-methyl-d-aspartate-dependent mechanisms. Mol Pharmacol 70, 1246-1254 70 (2006).
69. Dansereau M. A., Gosselin, R. D., Pohl, M., Pommier, B., Mechighel, P., Mauborgne, A., Rostene, W., Kitabgi, P., Beaudet, N., Sarret, P., and Melik-Parsadaniantz, S. Spinal ccl2 pronociceptive action is no longer effective in ccr2 receptor antagonist-treated rats. J Neurochem 106, 757-769 106 (2008).
70. Thacker M. A., Clark, A. K., Bishop, T., Grist, J., Yip, P. K., Moon, L. D., Thompson, S. W., Marchand, F., and McMahon, S. B. Ccl2 is a key mediator of microglia activation in neuropathic pain states. Eur J Pain 13, 263-272 13 (2009).
71. Chen J. J., Lue, J. H., Lin, L. H., Huang, C. T., Chiang, R. P., Chen, C. L., and Tsai, Y. J. Effects of pre-emptive drug treatment on astrocyte activation in the cuneate nucleus following rat median nerve injury. Pain (2009).
72. Chneiweiss H., Glowinski, J., and Premont, J. Modulation by monoamines of somatostatin-sensitive adenylate cyclase on neuronal and glial cells from the mouse brain in primary cultures. J Neurochem 44, 1825-1831 44 (1985).
73. Cholewinski A. J., Hanley, M. R., and Wilkin, G. P. A phosphoinositide-linked peptide response in astrocytes: Evidence for regional heterogeneity. Neurochem Res 13, 389-394 13 (1988).
74. el-Etr M., Cordier, J., Torrens, Y., Glowinski, J., and Premont, J. Pharmacological and functional heterogeneity of astrocytes: Regional differences in phospholipase c stimulation by neuromediators. J Neurochem 52, 981-984 52 (1989).
75. Palma C., Minghetti, L., Astolfi, M., Ambrosini, E., Silberstein, F. C., Manzini, S., Levi, G., and Aloisi, F. Functional characterization of substance p receptors on cultured human spinal cord astrocytes: Synergism of substance p with cytokines in inducing interleukin-6 and prostaglandin e2 production. Glia 21, 183-193 21 (1997).
76. Lazar P., Reddington, M., Streit, W., Raivich, G., and Kreutzberg, G. W. The action of calcitonin gene-related peptide on astrocyte morphology and cyclic amp accumulation in astrocyte cultures from neonatal rat brain. Neurosci Lett 130, 99-102 130 (1991).
77. Neary J. T., Baker, L., Jorgensen, S. L., and Norenberg, M. D. Extracellular atp induces stellation and increases glial fibrillary acidic protein content and DNA synthesis in primary astrocyte cultures. Acta Neuropathol 87, 8-13 87 (1994).
78. Noble L. J., Hall, J. J., Chen, S., and Chan, P. H. Morphologic changes in cultured astrocytes after exposure to glutamate. J Neurotrauma 9, 255-267 9 (1992).
79. Duan S., Anderson, C. M., Keung, E. C., Chen, Y., Chen, Y., and Swanson, R. A. P2x7 receptor-mediated release of excitatory amino acids from astrocytes. J Neurosci 23, 1320-1328 23 (2003).
80. Werry E. L., Liu, G. J., and Bennett, M. R. Glutamate-stimulated atp release from spinal cord astrocytes is potentiated by substance p. J Neurochem 99, 924-936 99 (2006). An elegant study on the cooperation between glutamate and SP in eliciting ATP release from spinal astrocytes.
81. Ziak D., Chvatal, A., and Sykova, E. Glutamate-, kainate- and nmdaevoked membrane currents in identified glial cells in rat spinal cord slice. Physiol Res 47, 365-375 47 (1998).
82. Pangrsic T., Potokar, M., Stenovec, M., Kreft, M., Fabbretti, E., Nistri, A., Pryazhnikov, E., Khiroug, L., Giniatullin, R., and Zorec, R. Exocytotic release of atp from cultured astrocytes. J Biol Chem 282, 28749-28758 282 (2007).
83. Queiroz G., Gebicke-Haerter, P. J., Schobert, A., Starke, K., and von Kugelgen, I. Release of atp from cultured rat astrocytes elicited by glutamate receptor activation. Neuroscience 78, 1203-1208 78 (1997).
84. Ahmed Z., Lewis, C. A., and Faber, D. S. Glutamate stimulates release of ca2+ from internal stores in astroglia. Brain Res 516, 165-169 516 (1990).
85. Abbracchio M. P., Burnstock, G., Verkhratsky, A., and Zimmermann, H. Purinergic signalling in the nervous system: An overview. Trends Neurosci 32, 19-29 32 (2009).
86. Priller J., Reddington, M., Haas, C. A., and Kreutzberg, G. W. Stimulation of p2y-purinoceptors on astrocytes results in immediate early gene expression and potentiation of neuropeptide action. Neuroscience 85, 521-525 85 (1998).
87. Anderson C. M., Bergher, J. P., and Swanson, R. A. Atp-induced atp release from astrocytes. J Neurochem 88, 246-256 88 (2004).
88. Inagaki N., Fukui, H., Ito, S., and Wada, H. Type-2 astrocytes show intra-cellular ca2+ elevation in response to various neuroactive substances. Neurosci Lett 128, 257-260 128 (1991).
89. Stevens B., and Fields, R. D. Response of schwann cells to action potentials in development. Science 287, 2267-2271 287 (2000).
90. Hald A. Spinal astrogliosis in pain models: Cause and effects. Cell Mol Neurobiol 29, 609-619 29 (2009).
91. Guthrie P. B., Knappenberger, J., Segal, M., Bennett, M. V., Charles, A. C., and Kater, S. B. Atp released from astrocytes mediates glial calcium waves. J Neurosci 19, 520-528 19 (1999).
92. Gallagher C. J., and Salter, M. W. Differential properties of astrocyte calcium waves mediated by p2y1 and p2y2 receptors. J Neurosci 23, 6728-6739 23 (2003).
93. Too H. P., Marriott, D. R., and Wilkin, G. P. Preprotachykinin-a and substance p receptor (nk1) gene expression in rat astrocytes in vitro. Neurosci Lett 182, 185-187 182 (1994).
94. Torrens Y., Daguet De Montety, M. C., el Etr, M., Beaujouan, J. C., and Glowinski, J. Tachykinin receptors of the nk1 type (substance p) coupled positively to phospholipase c on cortical astrocytes from the newborn mouse in primary culture. J Neurochem 52, 1913-1918 52 (1989).
95. Mantyh P. W., Johnson, D. J., Boehmer, C. G., Catton, M. D., Vinters, H. V., Maggio, J. E., Too, H. P., and Vigna, S. R. Substance p receptor binding sites are expressed by glia in vivo after neuronal injury. Proc Natl Acad Sci U S A 86, 5193-5197 86 (1989).
96. Marriott D., Wilkin, G. P., Coote, P. R., and Wood, J. N. Eicosanoid synthesis by spinal cord astrocytes is evoked by substance p; possible implications for nociception and pain. Adv Prostaglandin Thromboxane Leukot Res 21B, 739-741 21B (1991).
97. Brahmachari S., Fung, Y. K., and Pahan, K. Induction of glial fibrillary acidic protein expression in astrocytes by nitric oxide. J Neurosci 26, 4930-4939 26 (2006).
98. Vruwink M., Schmidt, H. H., Weinberg, R. J., and Burette, A. Substance p and nitric oxide signaling in cerebral cortex: Anatomical evidence for reciprocal signaling between two classes of interneurons. J Comp Neurol 441, 288-301 441 (2001).
99. Benemei S., Nicoletti, P., Capone, J. G., and Geppetti, P. Cgrp receptors in the control of pain and inflammation. Curr Opin Pharmacol 9, 9-14 9 (2009).
100. Haas C. A., Reddington, M., and Kreutzberg, G. W. Calcitonin generelated peptide stimulates the induction of c-fos gene expression in rat astrocyte cultures. Eur J Neurosci 3, 708-712 3 (1991).
101. White F. A., Feldman, P., and Miller, R. J. Chemokine signaling and the management of neuropathic pain. Mol Interv 9, 188-195 9 (2009).
102. Miller R. J., Rostene, W., Apartis, E., Banisadr, G., Biber, K., Milligan, E. D., White, F. A., and Zhang, J. Chemokine action in the nervous system. J Neurosci 28, 11792-11795 28 (2008).
103. White F. A., Bhangoo, S. K., and Miller, R. J. Chemokines: Integrators of pain and inflammation. Nat Rev Drug Discov 4, 834-844 4 (2005).
104. El-Hage N., Wu, G., Ambati, J., Bruce-Keller, A. J., Knapp, P. E., and Hauser, K. F. Ccr2 mediates increases in glial activation caused by exposure to hiv-1 tat and opiates. J Neuroimmunol 178, 9-16 178 (2006).
105. Abbadie C., Lindia, J. A., Cumiskey, A. M., Peterson, L. B., Mudgett, J. S., Bayne, E. K., DeMartino, J. A., MacIntyre, D. E., and Forrest, M. J. Impaired neuropathic pain responses in mice lacking the chemokine receptor ccr2. Proc Natl Acad Sci U S A 100, 7947-7952 100 (2003).
106. Shan S., Hong, C., Mei, H., Ting-Ting, L., Hai-Li, P., Zhi-Qi, Z., and Yu-Qiu, Z. New evidence for the involvement of spinal fractalkine receptor in pain facilitation and spinal glial activation in rat model of monoarthritis. Pain (2006).
107. Clark A. K., Yip, P. K., Grist, J., Gentry, C., Staniland, A. A., Marchand, F., Dehvari, M., Wotherspoon, G., Winter, J., Ullah, J., Bevan, S., and Malcangio, M. Inhibition of spinal microglial cathepsin s for the reversal of neuropathic pain. Proc Natl Acad Sci U S A 104, 10655-10660 104 (2007).
108. Milligan E. D., Zapata, V., Chacur, M., Schoeniger, D., Biedenkapp, J., O'Connor, K. A., Verge, G. M., Chapman, G., Green, P., Foster, A. C., Naeve, G. S., Maier, S. F., and Watkins, L. R. Evidence that exogenous and endogenous fractalkine can induce spinal nociceptive facilitation in rats. Eur J Neurosci 20, 2294-2302 20 (2004).
109. Lindia J. A., McGowan, E., Jochnowitz, N., and Abbadie, C. Induction of cx3cl1 expression in astrocytes and cx3cr1 in microglia in the spinal cord of a rat model of neuropathic pain. J Pain 6, 434-438 6 (2005).
110. Verge G. M., Milligan, E. D., Maier, S. F., Watkins, L. R., Naeve, G. S., and Foster, A. C. Fractalkine (cx3cl1) and fractalkine receptor (cx3cr1) distribution in spinal cord and dorsal root ganglia under basal and neuropathic pain conditions. Eur J Neurosci 20, 1150-1160 20 (2004).
111. Watkins L. R., Milligan, E. D., and Maier, S. F. Spinal cord glia: New players in pain. Pain 93, 201-205 93 (2001).
112. DeLeo J. A., Colburn, R. W., and Rickman, A. J. Cytokine and growth factor immunohistochemical spinal profiles in two animal models of mononeuropathy. Brain Res 759, 50-57 759 (1997).
113. Watkins L. R., Martin, D., Ulrich, P., Tracey, K. J., and Maier, S. F. Evidence for the involvement of spinal cord glia in subcutaneous formalin induced hyperalgesia in the rat. Pain 71, 225-235 71 (1997).
114. Reeve A. J., Patel, S., Fox, A., Walker, K., and Urban, L. Intrathecally administered endotoxin or cytokines produce allodynia, hyperalgesia and changes in spinal cord neuronal responses to nociceptive stimuli in the rat. Eur J Pain 4, 247-257 4 (2000).
115. Kawasaki Y., Zhang, L., Cheng, J. K., and Ji, R. R. Cytokine mechanisms of central sensitization: Distinct and overlapping role of interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha in regulating synaptic and neuronal activity in the superficial spinal cord. J Neurosci 28, 5189-5194 28 (2008).
116. Svensson C. I., Schafers, M., Jones, T. L., Powell, H., and Sorkin, L. S. Spinal blockade of tnf blocks spinal nerve ligation-induced increases in spinal p-p38. Neurosci Lett 379, 209-213 379 (2005).
117. Wieseler-Frank J., Maier, S. F., and Watkins, L. R. Central proinflammatory cytokines and pain enhancement. Neurosignals 14, 166-174 14 (2005). This article gives a historical view of glia and pain and discusses the evidence for an important role of centrally released cytokines in experimental models of prolonged pain states.
118. Arruda J. L., Sweitzer, S., Rutkowski, M. D., and DeLeo, J. A. Intrathecal anti-il-6 antibody and igg attenuates peripheral nerve injury-induced mechanical allodynia in the rat: Possible immune modulation in neuropathic pain. Brain Res 879, 216-225 879 (2000).
119. Falchi M., Ferrara, F., Gharib, C., and Dib, B. Hyperalgesic effect of intrathecally administered interleukin-1 in rats. Drugs Exp Clin Res 27, 97-101 27 (2001).
120. Li A., Lao, L., Wang, Y., Zhang, H., Ren, K., Berman, B. M., and Zhang, R. Interleukin-1ra inhibits fos expression and hyperalgesia in rats. Neuroreport 18, 495-498 18 (2007).
121. Narita M., Shimamura, M., Imai, S., Kubota, C., Yajima, Y., Takagi, T., Shiokawa, M., Inoue, T., Suzuki, M., and Suzuki, T. Role of interleukin-1beta and tumor necrosis factor-alpha-dependent expression of cyclooxygenase-2 mrna in thermal hyperalgesia induced by chronic inflammation in mice. Neuroscience 152, 477-486 152 (2008).
122. Raghavendra V., Tanga, F. Y., and DeLeo, J. A. Complete freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the cns. Eur J Neurosci 20, 467-473 20 (2004).
123. Zhang R. X., Li, A., Liu, B., Wang, L., Ren, K., Zhang, H., Berman, B. M., and Lao, L. Il-1ra alleviates inflammatory hyperalgesia through preventing phosphorylation of nmda receptor nr-1 subunit in rats. Pain 135, 232-239 135 (2008).
124. Clark A. K., D'Aquisto, F., Gentry, C., Marchand, F., McMahon, S. B., and Malcangio, M. Rapid co-release of interleukin 1beta and caspase 1 in spinal cord inflammation. J Neurochem 99, 868-880 99 (2006).
125. Van Dam A. M., Bauer, J., Tilders, F. J., and Berkenbosch, F. Endotoxin-induced appearance of immunoreactive interleukin-1 beta in ramified microglia in rat brain: A light and electron microscopic study. Neuroscience 65, 815-826 65 (1995).
126. Yang S., Liu, Z. W., Wen, L., Qiao, H. F., Zhou, W. X., and Zhang, Y. X. Interleukin-1beta enhances nmda receptor-mediated current but inhibits excitatory synaptic transmission. Brain Res 1034, 172-179 1034 (2005).
127. Tadano T., Namioka, M., Nakagawasai, O., Tan-No, K., Matsushima, K., Endo, Y., and Kisara, K. Induction of nociceptive responses by intrathecal injection of interleukin-1 in mice. Life Sci 65, 255-261 65 (1999).
128. Milligan E. D., O'Connor, K. A., Nguyen, K. T., Armstrong, C. B., Twining, C., Gaykema, R. P., Holguin, A., Martin, D., Maier, S. F., and Watkins, L. R. Intrathecal hiv-1 envelope glycoprotein gp120 induces enhanced pain states mediated by spinal cord proinflammatory cytokines. J Neurosci 21, 2808-2819 21 (2001).
129. Samad T. A., Moore, K. A., Sapirstein, A., Billet, S., Allchorne, A., Poole, S., Bonventre, J. V., and Woolf, C. J. Interleukin-1beta-mediated induction of cox-2 in the cns contributes to inflammatory pain hypersensitivity. Nature 410, 471-475 410 (2001).
130. Van Eldik L. J., and Zimmer, D. B. Secretion of s-100 from rat c6 glioma cells. Brain Res 436, 367-370 436 (1987).
131. Zimmer D. B., and Van Eldik, L. J. Tissue distribution of rat s100 alpha and s100 beta and s100-binding proteins. Am J Physiol 252, C285-289 252 (1987).
132. Svensson C. I., and Yaksh, T. L. The spinal phospholipase-cyclooxygenase- prostanoid cascade in nociceptive processing. Annu Rev Pharmacol Toxicol 42, 553-583 42 (2002).
133. Shanmugam N., Kim, Y. S., Lanting, L., and Natarajan, R. Regulation of cyclooxygenase-2 expression in monocytes by ligation of the receptor for advanced glycation end products. J Biol Chem 278, 34834-34844 278 (2003).
134. Nishiyama H., Knopfel, T., Endo, S., and Itohara, S. Glial protein s100b modulates long-term neuronal synaptic plasticity. Proc Natl Acad Sci U S A 99, 4037-4042 99 (2002).
135. Tanga F. Y., Raghavendra, V., Nutile-McMenemy, N., Marks, A., and Deleo, J. A. Role of astrocytic s100beta in behavioral hypersensitivity in rodent models of neuropathic pain. Neuroscience (2006).
136. Regan M. R., Huang, Y. H., Kim, Y. S., Dykes-Hoberg, M. I., Jin, L., Watkins, A. M., Bergles, D. E., and Rothstein, J. D. Variations in promoter activity reveal a differential expression and physiology of glutamate transporters by glia in the developing and mature cns. J Neurosci 27, 6607-6619 27 (2007).
137. Sung B., Wang, S., Zhou, B., Lim, G., Yang, L., Zeng, Q., Lim, J. A., Wang, J. D., Kang, J. X., and Mao, J. Altered spinal arachidonic acid turnover after peripheral nerve injury regulates regional glutamate concentration and neuropathic pain behaviors in rats. Pain 131, 121-131 131 (2007).
138. Wang S., Lim, G., Yang, L., Sung, B., and Mao, J. Downregulation of spinal glutamate transporter eaac1 following nerve injury is regulated by central glucocorticoid receptors in rats. Pain 120, 78-85 120 (2006).
139. Binns B. C., Huang, Y., Goettl, V. M., Hackshaw, K. V., and Stephens, R. L., Jr. Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model. Brain Res 1041, 38-47 1041 (2005).
140. Tawfik V. L., Regan, M. R., Haenggeli, C., Lacroix-Fralish, M. L., Nutile-McMenemy, N., Perez, N., Rothstein, J. D., and DeLeo, J. A. Propentofylline-induced astrocyte modulation leads to alterations in glial glutamate promoter activation following spinal nerve transection. Neuroscience 152, 1086-1092 152 (2008).
141. Xin W. J., Weng, H. R., and Dougherty, P. M. Plasticity in expression of the glutamate transporters glt-1 and glast in spinal dorsal horn glial cells following partial sciatic nerve ligation. Mol Pain 5, 15 5 (2009).
142. Weng H. R., Aravindan, N., Cata, J. P., Chen, J. H., Shaw, A. D., and Dougherty, P. M. Spinal glial glutamate transporters downregulate in rats with taxol-induced hyperalgesia. Neurosci Lett 386, 18-22 386 (2005).
143. Maeda S., Kawamoto, A., Yatani, Y., Shirakawa, H., Nakagawa, T., and Kaneko, S. Gene transfer of glt-1, a glial glutamate transporter, into the spinal cord by recombinant adenovirus attenuates inflammatory and neuropathic pain in rats. Mol Pain 4, 65 4 (2008).
144. Sonnewald U., Westergaard, N., and Schousboe, A. Glutamate transport and metabolism in astrocytes. Glia 21, 56-63 21 (1997).
145. Jourdain P., Bergersen, L. H., Bhaukaurally, K., Bezzi, P., Santello, M., Domercq, M., Matute, C., Tonello, F., Gundersen, V., and Volterra, A. Glutamate exocytosis from astrocytes controls synaptic strength. Nat Neurosci 10, 331-339 10 (2007). This study provides the first combined functional and ultrastructural evidence for release of glutamate from astrocytes and point to an important role for astrocytes in the control of synaptic activity.
146. Perea G., and Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083-1086 317 (2007).
147. Allen N. J., and Barres, B. A. Signaling between glia and neurons: Focus on synaptic plasticity. Curr Opin Neurobiol 15, 542-548 15 (2005).
148. Christopherson K. S., Ullian, E. M., Stokes, C. C., Mullowney, C. E., Hell, J. W., Agah, A., Lawler, J., Mosher, D. F., Bornstein, P., and Barres, B. A. Thrombospondins are astrocyte-secreted proteins that promote cns synaptogenesis. Cell 120, 421-433 120 (2005).
149. Nishida H., and Okabe, S. Direct astrocytic contacts regulate local maturation of dendritic spines. J Neurosci 27, 331-340 27 (2007).
150. Haber M., Zhou, L., and Murai, K. K. Cooperative astrocyte and dendritic spine dynamics at hippocampal excitatory synapses. J Neurosci 26, 8881-8891 26 (2006).
151. Carmona M. A., Murai, K. K., Wang, L., Roberts, A. J., and Pasquale, E. B. Glial ephrin-a3 regulates hippocampal dendritic spine morphology and glutamate transport. Proc Natl Acad Sci U S A 106, 12524-12529 106 (2009).
152. Eroglu C., Allen, N. J., Susman, M. W., O'Rourke, N. A., Park, C. Y., Ozkan, E., Chakraborty, C., Mulinyawe, S. B., Annis, D. S., Huberman, A. D., Green, E. M., Lawler, J., Dolmetsch, R., Garcia, K. C., Smith, S. J., Luo, Z. D., Rosenthal, A., Mosher, D. F., and Barres, B. A. Gabapentin receptor alpha2delta-1 is a neuronal thrombospondin receptor responsible for excitatory cns synaptogenesis. Cell 139, 380-392 139 (2009).
153. Davies A., Hendrich, J., Van Minh, A. T., Wratten, J., Douglas, L., and Dolphin, A. C. Functional biology of the alpha(2)delta subunits of voltage-gated calcium channels. Trends Pharmacol Sci 28, 220-228 28 (2007).
154. Zanella J. M., Burright, E. N., Hildebrand, K., Hobot, C., Cox, M., Christoferson, L., and McKay, W. F. Effect of etanercept, a tumor necrosis factor-alpha inhibitor, on neuropathic pain in the rat chronic constriction injury model. Spine (Phila Pa 1976) 33, 227-234 33 (2008).
155. Svensson C. I., Zattoni, M., and Serhan, C. N. Lipoxins and aspirintriggered lipoxin inhibit inflammatory pain processing. J Exp Med 204, 245-252 204 (2007).
156. Milligan E. D., and Watkins, L. R. Pathological and protective roles of glia in chronic pain. Nat Rev Neurosci 10, 23-36 10 (2009).