Top

Published in:

Open Access 01-12-2005 | Review

Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states

Authors: Yuan-Xiang Tao, Jianguo Gu, Robert L Stephens Jr

Published in: Molecular Pain | Issue 1/2005

Abstract

Glutamate is a neurotransmitter critical for spinal excitatory synaptic transmission and for generation and maintenance of spinal states of pain hypersensitivity via activation of glutamate receptors. Understanding the regulation of synaptically and non-synaptically released glutamate associated with pathological pain is important in exploring novel molecular mechanisms and developing therapeutic strategies of pathological pain. The glutamate transporter system is the primary mechanism for the inactivation of synaptically released glutamate and the maintenance of glutamate homeostasis. Recent studies demonstrated that spinal glutamate transporter inhibition relieved pathological pain, suggesting that the spinal glutamate transporter might serve as a therapeutic target for treatment of pathological pain. However, the exact function of glutamate transporter in pathological pain is not completely understood. This report will review the evidence for the role of the spinal glutamate transporter during normal sensory transmission and pathological pain conditions and discuss potential mechanisms by which spinal glutamate transporter is involved in pathological pain.

Available only for authorised users

Mayer BL, Westbrook GL: The physiology of excitatory amino acids in the vertebrate central nervous system. Prog Neurobiol 1987, 28: 197–276. 10.1016/0301-0082(87)90011-6PubMedCrossRef

Basbaum AI, Woolf CJ: Pain. Curr Biol 1999, 9: R429–431. 10.1016/S0960-9822(99)80273-5PubMedCrossRef

Danbolt NC: Glutamate uptake. Prog Neurobiol 2001, 65: 1–105. 10.1016/S0301-0082(00)00067-8PubMedCrossRef

Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D, Nash N, Kuncl RW: Localization of neuronal and glial glutamate transporter. Neurons 1994, 13: 713–725. 10.1016/0896-6273(94)90038-8CrossRef

Kugler P, Schmitt A: Glutamate transporter EAAC1 is expressed in neurons and glial cells in the rat nervous system. Glia 1999, 27: 129–142. 10.1002/(SICI)1098-1136(199908)27:2<129::AID-GLIA3>3.0.CO;2-YPubMedCrossRef

Dehnes Y, Chaudhry FA, Ullensvang K, Lehre KP, Storm-Mathisen J, Nanbolt NC: The glutamate transporter EAAT4 in rat cerebellar Purkinje cells: a glutamate-gated chloride channel concentrated near the synapses in parts of the dendritic membrane facing astroglia. J Neurosci 1998, 18: 3606–3619.PubMed

Arriza JL, Eliasof S, Kavanaugh MP, Amara SG: Excitatory amino acid 5, a retinal glutamate transporter coupled to a chloride conductance. Proc Natl Sci USA 1997, 94: 4155–4160. 10.1073/pnas.94.8.4155CrossRef

Liaw WJ, Stephens RL Jr, Binns BC, Chu Y, Sepkuty JP, Johns RA, Rothstein JD, Tao Y-X: Spinal glutamate uptake is critical for maintaining normal sensory transmission in rat spinal cord. Pain 2005, 115: 60–70. 10.1016/j.pain.2005.02.006PubMedCrossRef

Minami T, Matsumura S, Okuda-Ashitaka E, Shimamoto K, Sakimura K, Mishina M, Mori H, Ito S: Characterization of the glutamatergic system for induction and maintenance of allodynia. Brain Res 2001, 895: 178–85. 10.1016/S0006-8993(01)02069-8PubMedCrossRef

10.

Niederberger E, Schmidtko A, Rothstein JD, Geisslinger G, Tegeder I: Modulation of spinal nociceptive processing through the glutamate transporter GLT-1. Neurosci 2003, 116: 81–87. 10.1016/S0306-4522(02)00547-XCrossRef

11.

Tao Y-X, Tao F, Liaw WJ, Zhang B, Yaster M, Rothstein JD, Johns RA: Evidence for the involvement of spinal cord glutamate transporters in the development of chronic inflammatory pain. ASA 2003 Annual Meeting. San Francisco, CA, USA Oct. 12–16, 2003

12.

Tao F, Liaw WJ, Zhang B, Yaster M, Rothstein JD, Johns RA, Tao Y-X: Evidence of neuronal excitatory amino acid carrier 1 expression in rat dorsal root ganglion neurons and their central terminals. Neuroscience 2004, 123: 1045–51. 10.1016/j.neuroscience.2003.11.026PubMedCrossRef

13.

Tao Y-X, Petralia RS, Liaw W-J, Zhang B, Johns RA, Rothstein JD: Expression and distribution of glutamate transporters in the spinal cord and dorsal root ganglion. Soc Neurosci Abstract 2004. Program No. 484.5

14.

Aanonsen LM, Wilcox GL: Nociceptive action of excitatory amino acids in the mouse: effects of spinally administered opioids, phencyclidine and sigma agonists. J Pharmcol Exp Ther 1987, 243: 9–19.

15.

Brambilla A, Prudentino A, Grippa N, Borsini F: Pharmacological characterization of AMPA-induced biting behaviour in mice. Europ J Pharmacol 1996, 305: 115–7. 10.1016/0014-2999(96)00145-8CrossRef

16.

Kontinen VK, Meert TF: Vocalization responses after intrathecal administration of ionotropic glutamate receptor agonists in rats. Anesth Analg 2002, 95: 997–1001. 10.1097/00000539-200210000-00038PubMed

17.

Weng H, Cata J, Dougherty P: Glutamate transporters play a key role in sensory transmission of the spinal dorsal horn. J Pain 2004, (Suppl 5):5. 10.1016/j.jpain.2004.02.557

18.

Weng H, Chen J, Cata J, Dougherty P: Inhibition of glutamate transporters increases hind paw withdrawal frequencies and dorsal horn neurons responses to peripheral stimuli in rats. Soc Neurosci Abstr 2004. Program No 291.6

19.

Shimamoto K, Lebrun B, Yasuda-Kamatani Y, Sakaitani M, Shigeri Y, Yumoto N, Nakajima T: DL-TBOA, a potent blocker of excitatory amino acid transporters. Mol Pharmacol 1998, 53: 195–201.PubMed

20.

Phillis JW, Ren J, O'Regan MH: Transporter reversal as a mechanism of glutamate release from the ischemic rat cerebral cortex: studies with DL-TBOA. Brain Res 2000, 868: 105–12. 10.1016/S0006-8993(00)02303-9PubMedCrossRef

21.

Sung B, Lim G, Mao J: Altered expression and uptake activity of spinal glutamate transporters after nerve injury contribute to the pathogenesis of neuropathic pain in rats. J Neurosci 2003, 23: 2899–910.PubMed

22.

Binns BC, Huang Y, Goettl VM, Hackshaw KV, Stephens RL Jr: Glutamate uptake is attenuated in spinal deep dorsal and ventral horn in the rat spinal nerve ligation model. Brain Res 2005, 1041: 38–47. 10.1016/j.brainres.2005.01.088PubMedCrossRef

23.

Umemura K, Gemba T, Mizuno A, Nakashima M: Inhibitory effect of MS-153 on elevated brain glutamate level induced by rat middle cerebral artery occlusion. Stroke 1996, 27: 1624–8.PubMedCrossRef

24.

Shimada F, Shiga Y, Morikawa M, Kawazura H, Morikawa O, Matsuoka T, Nishizaki T, Saito N: The neuroprotective agent MS-153 stimulates glutamate uptake. Eur J Pharmacol 1999, 386: 263–70. 10.1016/S0014-2999(99)00735-9PubMedCrossRef

25.

Abekawa T, Honda M, Ito K, Inoue T, Koyama T: Effect of MS-153 on the development of behavioral sensitization to locomotion- and ataxia-inducing effects of phencyclidine. Psychopharmacology (Berl) 2002, 160: 122–31. 10.1007/s00213-001-0958-1CrossRef

26.

Abekawa T, Honda M, Ito K, Inoue T, Koyama T: Effect of MS-153 on the development of behavioral sensitization to stereotypy-inducing effect of phencyclidine. Brain Res 2002, 926: 176–80. 10.1016/S0006-8993(01)03164-XPubMedCrossRef

27.

Galer BS, Twilling LL, Harle J, Cluff RS, Friedman E, Rowbotham MC: Lack of efficacy of riluzole in the treatment of peripheral neuropathic pain conditions. Neurology 2000, 55: 971–5.PubMedCrossRef

28.

Kretschmer BD, Kratzer U, Schmidt WJ: Riluzole, a glutamate release inhibitor, and motor behavior. Naunyn Schmiedebergs Arch Pharmacol 1998, 358: 181–90.PubMedCrossRef

29.

Hebert T, Drapeau P, Pradier L, Dunn RJ: Block of the rat brain IIA sodium channel alpha subunit by the neuroprotective drug riluzole. Mol Pharmacol 1994, 45: 1055–60.PubMed

30.

Mantz J: Riluzole. CNS Drug Rev 1996, 2: 40–51.CrossRef

31.

Azbill RD, Mu X, Springer JE: Riluzole increases high-affinity glutamate uptake in rat spinal cord synaptosomes. Brain Res 2000, 871: 175–80. 10.1016/S0006-8993(00)02430-6PubMedCrossRef

32.

Mathews GC, Diamond JS: Neuronal glutamate uptake contributes to GABA synthesis and inhibitory synaptic strength. J Neurosci 2003, 23: 040–8.

33.

Rae C, Hare N, Bubb WA, McEwan SR, Broer A, McQuillan JA, Balcar VJ, Conigrave AD, Broer S: Inhibition of glutamine transport depletes glutamate and GABA neurotransmitter pools: further evidence for metabolic compartmentation. J Neurochem 2003, 85: 503–14.PubMedCrossRef

34.

Ottersen OP, Laake JH, Reichelt W, Haug FM, Torp R: Ischemic disruption of glutamate homeostasis in brain: quantitative immunocytochemical analysis. J Chem Neuroanat 1996, 12: 1–14. 10.1016/S0891-0618(96)00178-0PubMedCrossRef

35.

Storm-Mathisen J, Zhang N, Ottersen OP: Electron microscopic localization of glutamate, glutamine and GABA at putative glutamatergic and GABAergic synapses. Mol Neuropharmacol 1992, 2: 7–13.

36.

Broman J, Hassel B, Rinvik E, Ottersen OP: Biochemistry and anatomy of transmitter glutamate. In Glutamate. Edited by: Ottensen OP, Storm-Mathisen J. Elsevier, Amsterdam; 2000:1–44.CrossRef

37.

Hassel B, Brathe A: Cerebral metabolism of lactate in vivo: evidence for neuronal pyruvate carboxylation. J Cereb Blood Flow Metab 2000, 20: 327–336. 10.1097/00004647-200002000-00014PubMedCrossRef

38.

Hassel B, Brathe A: Neuronal pyruvate carboxylation supports formation of transmitter glutamate. J Neurosci 2000, 20: 1342–1347.PubMed

39.

Scanziani M, Salin PA, Vogt KE, Malenka RC, Nicoll RA: Use-dependent increases in glutamate concentration activate presynaptic metabotropic glutamate receptors. Nature 1997, 385: 630–4. 10.1038/385630a0PubMedCrossRef

40.

Maki R, Robinson MB, Dichter MA: The glutamate uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate depresses excitatory synaptic transmission via a presynaptic mechanism in cultured hippocampal neurons. J Neurosci 1994, 14: 6754–6762.PubMed

41.

Dube GR, Marshall KC: Activity-dependent activation of presynaptic metabotropic glutamate receptors in locus coeruleus. J Neurophysiol 2000, 83: 1141–1149.PubMed

42.

Nicholls D, Attwell D: The release and uptake of excitatory amino acids. Trends Pharmacol Sci 1990, 11: 462–8. 10.1016/0165-6147(90)90129-VPubMedCrossRef

43.

Erecinska M: Stimulation of the Na+/K+ pump activity during electrogenic uptake of acidic amino acid transmitters by rat brain synaptosomes. J Neurochem 1989, 52: 135–9.PubMedCrossRef

44.

Sarantis M, Attwell D: Glutamate uptake in mammalian retinal glia is voltage- and potassium-dependent. Brain Res 1990, 516: 322–5. 10.1016/0006-8993(90)90935-5PubMedCrossRef

45.

Vikman KS, Duggan AW, Siddall PJ: Increased ability to induce long-term potentiation of spinal dorsal horn neurones in monoarthritic rats. Brain Res 2003, 990: 51–7. 10.1016/S0006-8993(03)03385-7PubMedCrossRef

46.

Wieseler-Frank J, Maier SF, Watkins LR: Glial activation and pathological pain. Neurochem Int 2004, 45: 389–95. 10.1016/j.neuint.2003.09.009PubMedCrossRef

47.

Schadrack J, Neto FL, Ableitner A, Castro-Lopes JM, Willoch F, Bartenstein P, Zieglgansberger W, Tolle TR: Metabolic activity changes in the rat spinal cord during adjuvant monoarthritis. Neuroscience 1999, 94: 595–605. 10.1016/S0306-4522(99)00186-4PubMedCrossRef

48.

Benani A, Vol C, Heurtaux T, Asensio C, Dauca M, Lapicque F, Netter P, Minn A: Up-regulation of fatty acid metabolizing-enzymes mRNA in rat spinal cord during persistent peripheral local inflammation. Eur J Neurosci 2003, 18: 1904–14. 10.1046/j.1460-9568.2003.02930.xPubMedCrossRef

Title: Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states
Authors: Yuan-Xiang Tao
Jianguo Gu
Robert L Stephens Jr
Publication date: 01-12-2005
Publisher: BioMed Central
Published in: Molecular Pain / Issue 1/2005
Electronic ISSN: 1744-8069
DOI: https://doi.org/10.1186/1744-8069-1-30

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Role of spinal cord glutamate transporter during normal sensory transmission and pathological pain states

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2005

Neuropathic pain develops normally in mice lacking both Nav1.7 and Nav1.8

Worm sensation!

Contrasting phenotypes of putative proprioceptive and nociceptive trigeminal neurons innervating jaw muscle in rat

Acidification of rat TRPV1 alters the kinetics of capsaicin responses

An efficient intrathecal delivery of small interfering RNA to the spinal cord and peripheral neurons

Increased glutamate synaptic transmission in the nucleus raphe magnus neurons from morphine-tolerant rats