Molecular Neurobiology

, Volume 40, Issue 3, pp 260–288 | Cite as

Ionotropic Glutamate Receptors in Spinal Nociceptive Processing

Article

Abstract

Glutamate is the predominant excitatory transmitter used by primary afferent synapses and intrinsic neurons in the spinal cord dorsal horn. Accordingly, ionotropic glutamate receptors mediate basal spinal transmission of sensory, including nociceptive, information that is relayed to supraspinal centers. However, it has become gradually more evident that these receptors are also crucially involved in short- and long-term plasticity of spinal nociceptive transmission, and that such plasticity have an important role in the pain hypersensitivity that may result from tissue or nerve injury. This review will cover recent findings on pre- and postsynaptic regulation of synaptic function by ionotropic glutamate receptors in the dorsal horn and how such mechanisms contribute to acute and chronic pain.

Keywords

Hyperalgesia Nociception AMPA receptors NMDA receptors Kainate receptors Long-term potentiation Presynaptic regulation Synaptic plasticity 

References

  1. 1.
    Perl ER (2007) Ideas about pain, a historical view. Nat Rev Neurosci 8:71–80PubMedGoogle Scholar
  2. 2.
    Craig AD (2003) Pain mechanisms: labeled lines versus convergence in central processing. Annu Rev Neurosci 26:1–30PubMedGoogle Scholar
  3. 3.
    Willis WD, Coggeshall RE (2004) Sensory mechanisms of the spinal cord. Kluwer, New YorkGoogle Scholar
  4. 4.
    Curtis DR, Phillis JW, Watkins JC (1959) Chemical excitation of spinal neurones. Nature 183:611–612PubMedGoogle Scholar
  5. 5.
    Watkins JC, Jane DE (2006) The glutamate story. Br J Pharmacol 147:S100–S108PubMedGoogle Scholar
  6. 6.
    Broman J, Rinvik E, Sassoè-Pognetto M, Shandiz HK, Ottersen OP (2004) Glutamate. In: Paxinos G (ed) The rat nervous system. Academic, San Diego, pp 1269–1292Google Scholar
  7. 7.
    Alvarez FJ, Villalba RM, Zerda R, Schneider SP (2004) Vesicular glutamate transporters in the spinal cord, with special reference to sensory primary afferent synapses. J Comp Neurol 472:257–280PubMedGoogle Scholar
  8. 8.
    Todd AJ, Hughes DI, Polgár E, Nagy GG, Mackie M, Ottersen OP, Maxwell DJ (2003) The expression of vesicular glutamate transporters VGLUT1 and VGLUT2 in neurochemically defined axonal populations in the rat spinal cord with emphasis on the dorsal horn. Eur J Neurosci 17:13–27PubMedGoogle Scholar
  9. 9.
    Broman J (1994) Neurotransmitters in subcortical somatosensory pathways. Anat Embryol 189:181–214PubMedGoogle Scholar
  10. 10.
    Broman J, Anderson S, Ottersen OP (1993) Enrichment of glutamate-like immunoreactivity in primary afferent terminals throughout the spinal cord dorsal horn. Eur J NeuroSci 5:1050–1061PubMedGoogle Scholar
  11. 11.
    Valtschanoff JG, Weinberg RJ, Rustioni A (1993) Amino acid immunoreactivity in corticospinal terminals. Exp Brain Res 93:95–103PubMedGoogle Scholar
  12. 12.
    Persson S, Boulland J-L, Aspling M, Larsson M, Fremeau RTJ, Edwards RH, Storm-Mathisen J, Chaudhry FA, Broman J (2006) Distribution of vesicular glutamate transporters 1 and 2 in the rat spinal cord, with a note on the spinocervical tract. J Comp Neurol 497:683–701PubMedGoogle Scholar
  13. 13.
    Djouhri L, Lawson SN (2004) Aβ-fiber nociceptive primary afferent neurons: a review of incidence and properties in relation to other afferent A-fiber neurons in mammals. Brain Res Brain Res Rev 46:131–145PubMedGoogle Scholar
  14. 14.
    Todd AJ, Koerber HR (2006) Neuroanatomical substrates of spinal nociception. In: McMahon SB, Koltzenburg M (eds) Wall and Melzack’s textbook of pain. Elsevier, Oxford, pp 73–90Google Scholar
  15. 15.
    Hunt SP, Mantyh PW (2001) The molecular dynamics of pain control. Nat Rev Neurosci 2:83–91PubMedGoogle Scholar
  16. 16.
    Price TJ, Flores CM (2007) Critical evaluation of the colocalization between calcitonin gene-related peptide, substance P, transient receptor potential vanilloid subfamily type 1 immunoreactivities, and isolectin B4 binding in primary afferent neurons of the rat and mouse. J Pain 8:263–272PubMedGoogle Scholar
  17. 17.
    Woodbury CJ, Zwick M, Wang S, Lawson JJ, Caterina MJ, Koltzenburg M, Albers KM, Koerber HR, Davis BM (2004) Nociceptors lacking TRPV1 and TRPV2 have normal heat responses. J Neurosci 24:6410–6415PubMedGoogle Scholar
  18. 18.
    Zwick M, Davis BM, Woodbury CJ, Burkett JN, Koerber HR, Simpson JF, Albers KM (2002) Glial cell line-derived neurotrophic factor is a survival factor for isolectin B4-positive, but not vanilloid receptor 1-positive, neurons in the mouse. J Neurosci 22:4057–4065PubMedGoogle Scholar
  19. 19.
    Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25PubMedGoogle Scholar
  20. 20.
    Dong X, Han S, Zylka MJ, Simon MI, Anderson DJ (2001) A diverse family of GPCRs expressed in specific subsets of nociceptive sensory neurons. Cell 106:619–632PubMedGoogle Scholar
  21. 21.
    Dussor G, Zylka MJ, Anderson DJ, McCleskey EW (2008) Cutaneous sensory neurons expressing the Mrgprd receptor sense extracellular ATP and are putative nociceptors. J Neurophysiol 99:1581–1589PubMedGoogle Scholar
  22. 22.
    Cavanaugh DJ, Lee H, Lo L, Shields SD, Zylka MJ, Basbaum AI, Anderson DJ (2009) Distinct subsets of unmyelinated primary sensory fibers mediate behavioral responses to noxious thermal and mechanical stimuli. Proc Natl Acad Sci USA 106:9075–9080PubMedGoogle Scholar
  23. 23.
    Guo A, Vulchanova L, Wang J, Li X, Elde R (1999) Immunocytochemical localization of the vanilloid receptor 1 (VR1): relationship to neuropeptides, the P2X3 purinoceptor and IB4 binding sites. Eur J NeuroSci 11:946–958PubMedGoogle Scholar
  24. 24.
    Michael GJ, Priestley JV (1999) Differential expression of the mRNA for the vanilloid receptor subtype 1 in cells of the adult rat dorsal root and nodose ganglia and its downregulation by axotomy. J Neurosci 19:1844–1854PubMedGoogle Scholar
  25. 25.
    Hwang SJ, Oh JM, Valtschanoff JG (2005) Expression of the vanilloid receptor TRPV1 in rat dorsal root ganglion neurons supports different roles of the receptor in visceral and cutaneous afferents. Brain Res 1047:261–266PubMedGoogle Scholar
  26. 26.
    Liu M, Willmott NJ, Michael GJ, Priestley JV (2004) Differential pH and capsaicin responses of Griffonia simplicifolia IB4 (IB4)-positive and IB4-negative small sensory neurons. Neuroscience 127:659–672PubMedGoogle Scholar
  27. 27.
    Tominaga M, Caterina MJ, Malmberg AB, Rosen TA, Gilbert H, Skinner K, Raumann BE, Basbaum AI, Julius D (1998) The cloned capsaicin receptor integrates multiple pain-producing stimuli. Neuron 21:531–543PubMedGoogle Scholar
  28. 28.
    Fang X, Djouhri L, McMullan S, Berry C, Waxman SG, Okuse K, Lawson SN (2006) Intense isolectin-B4 binding in rat dorsal root ganglion neurons distinguishes C-fiber nociceptors with broad action potentials and high Nav1.9 expression. J Neurosci 26:7281–7292PubMedGoogle Scholar
  29. 29.
    Ribeiro-da-Silva A (2004) Substantia gelatinosa of the spinal cord. In: Paxinos G (ed) The rat nervous system. Academic, San Diego, pp 129–148Google Scholar
  30. 30.
    Gerke MB, Plenderleith MB (2004) Ultrastructural analysis of the central terminals of primary sensory neurones labelled by transganglionic transport of bandeiraea simplicifolia i-isolectin B4. Neuroscience 127:165–175PubMedGoogle Scholar
  31. 31.
    Graham BA, Brichta AM, Callister RJ (2007) Moving from an averaged to specific view of spinal cord pain processing circuits. J Neurophysiol 98:1057–1063PubMedGoogle Scholar
  32. 32.
    Morris R, Cheunsuang O, Stewart A, Maxwell D (2004) Spinal dorsal horn neurone targets for nociceptive primary afferents: do single neurone morphological characteristics suggest how nociceptive information is processed at the spinal level. Brain Res Brain Res Rev 46:173–190PubMedGoogle Scholar
  33. 33.
    Todd AJ (2002) Anatomy of primary afferents and projection neurones in the rat spinal dorsal horn with particular emphasis on substance P and the neurokinin 1 receptor. Exp Physiol 87:245–249PubMedGoogle Scholar
  34. 34.
    Lu Y, Perl ER (2005) Modular organization of excitatory circuits between neurons of the spinal superficial dorsal horn (laminae I and II). J Neurosci 25:3900–3907PubMedGoogle Scholar
  35. 35.
    Maxwell DJ, Belle MD, Cheunsuang O, Stewart A, Morris R (2007) Morphology of inhibitory and excitatory interneurons in superficial laminae of the rat dorsal horn. J Physiol 584:521–533PubMedGoogle Scholar
  36. 36.
    Heinke B, Ruscheweyh R, Forsthuber L, Wunderbaldinger G, Sandkühler J (2004) Physiological, neurochemical and morphological properties of a subgroup of GABAergic spinal lamina II neurones identified by expression of green fluorescent protein in mice. J Physiol 560:249–266PubMedGoogle Scholar
  37. 37.
    Braz JM, Nassar MA, Wood JN, Basbaum AI (2005) Parallel "pain" pathways arise from subpopulations of primary afferent nociceptor. Neuron 47:787–793PubMedGoogle Scholar
  38. 38.
    Todd AJ (1996) GABA and glycine in synaptic glomeruli of the rat spinal dorsal horn. Eur J NeuroSci 8:2492–2498PubMedGoogle Scholar
  39. 39.
    Olave MJ, Puri N, Kerr R, Maxwell DJ (2002) Myelinated and unmyelinated primary afferent axons form contacts with cholinergic interneurons in the spinal dorsal horn. Exp Brain Res 145:448–456PubMedGoogle Scholar
  40. 40.
    Neumann S, Braz JM, Skinner K, Llewellyn-Smith IJ, Basbaum AI (2008) Innocuous, not noxious, input activates PKCγ interneurons of the spinal dorsal horn via myelinated afferent fibers. J Neurosci 28:7936–7944PubMedGoogle Scholar
  41. 41.
    Collingridge GL, Olsen RW, Peters J, Spedding M (2009) A nomenclature for ligand-gated ion channels. Neuropharmacology 56:2–5PubMedGoogle Scholar
  42. 42.
    Petralia RS, Wenthold RJ (2008) NMDA receptors. In: Gereau RW, Swanson GT (eds) The glutamate receptors. Humana, Totowa, pp 45–98Google Scholar
  43. 43.
    Yuan H, Geballe MT, Hansen KB, Traynelis SF (2008) Structure and function of the NMDA receptor. In: Hell JW, Ehlers MD (eds) Structural and functional organization of the synapse. Springer, New York, pp 290–316Google Scholar
  44. 44.
    Cull-Candy SG, Leszkiewicz DN (2004) Role of distinct NMDA receptor subtypes at central synapses. Sci STKE 2004, re16Google Scholar
  45. 45.
    Zukin RS, Bennett MVL (1995) Alternatively spliced isoforms of the NMDARI receptor subunit. Trends Neurosci 18:306–313PubMedGoogle Scholar
  46. 46.
    Gundersen V, Storm-Mathisen J (2000) Aspartate - neurochemical evidence for a transmitter role. In: Ottersen OP, Storm-Mathisen J (eds) Glutamate. Elsevier, Amsterdam, pp 45–62Google Scholar
  47. 47.
    Miyaji T, Echigo N, Hiasa M, Senoh S, Omote H, Moriyama Y (2008) Identification of a vesicular aspartate transporter. Proc Natl Acad Sci USA 105:11720–11724PubMedGoogle Scholar
  48. 48.
    Larsson M, Persson S, Ottersen OP, Broman J (2001) Quantitative analysis of immunogold labeling indicates low levels and non-vesicular localization of l-aspartate in rat primary afferent terminals. J Comp Neurol 430:147–159PubMedGoogle Scholar
  49. 49.
    Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51:7–62PubMedGoogle Scholar
  50. 50.
    Chatterton JE, Awobuluyi M, Premkumar LS, Takahashi H, Talantova M, Shin Y, Cui J, Tu S, Sevarino KA, Nakanishi N, Tong G, Lipton SA, Zhang D (2002) Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature 415:793–798PubMedGoogle Scholar
  51. 51.
    Cavara N, Hollmann M (2008) Shuffling the deck anew: how NR3 tweaks NMDA receptor function. Mol Neurobiol 38:16–26PubMedGoogle Scholar
  52. 52.
    Wenthold RJ, Al-Hallaq RA, Croft Swanwick C, Petralia RS (2008) Molecular properties and cell biology of the NMDA receptor. In: Hell JW, Ehlers MD (eds) Structural and functional organization of the synapse. Springer, New York, pp 317–367Google Scholar
  53. 53.
    Ashby MC, Daw MI, Isaac JTR (2008) AMPA receptors. In: Gereau RW, Swanson GT (eds) The glutamate receptors. Humana, Totowa, pp 1–44Google Scholar
  54. 54.
    Kessels HW, Malinow R (2009) Synaptic AMPA receptor plasticity and behavior. Neuron 61:340–350PubMedGoogle Scholar
  55. 55.
    Shepherd JD, Huganir RL (2007) The cell biology of synaptic plasticity: AMPA receptor trafficking. Annu Rev Cell Dev Biol 23:613–643PubMedGoogle Scholar
  56. 56.
    Cull-Candy S, Kelly L, Farrant M (2006) Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond. Curr Opin Neurobiol 16:288–297PubMedGoogle Scholar
  57. 57.
    Patneau DK, Mayer ML (1990) Structure-activity relationships for amino acid transmitter candidates acting at N-methyl-d-aspartate and quisqualate receptors. J Neurosci 10:2385–2399PubMedGoogle Scholar
  58. 58.
    Contractor A, Swanson GT (2008) Kainate receptors. In: Gereau RW, Swanson GT (eds) The glutamate receptors. Humana, Totowa, pp 1–44Google Scholar
  59. 59.
    Petralia RS, Yokotani N, Wenthold RJ (1994) Light and electron microscope distribution of the NMDA receptor subunit NMDAR1 in the rat nervous system using a selective anti-peptide antibody. J Neurosci 14:667–696PubMedGoogle Scholar
  60. 60.
    Petralia RS, Wang YX, Wenthold RJ (1994) The NMDA receptor subunits NR2A and NR2B show histological and ultrastructural localization patterns similar to those of NR1. J Neurosci 14:6102–6120PubMedGoogle Scholar
  61. 61.
    Watanabe M, Fukaya M, Sakimura K, Manabe T, Mishina M, Inoue Y (1998) Selective scarcity of NMDA receptor channel subunits in the stratum lucidum (mossy fibre-recipient layer) of the mouse hippocampal CA3 subfield. Eur J NeuroSci 10:478–487PubMedGoogle Scholar
  62. 62.
    Nagy GG, Watanabe M, Fukaya M, Todd AJ (2004) Synaptic distribution of the NR1, NR2A and NR2B subunits of the N-methyl-d-aspartate receptor in the rat lumbar spinal cord revealed with an antigen-unmasking technique. Eur J NeuroSci 20:3301–3312PubMedGoogle Scholar
  63. 63.
    Nagy GG, Al-Ayyan M, Andrew D, Fukaya M, Watanabe M, Todd AJ (2004) Widespread expression of the AMPA receptor GluR2 subunit at glutamatergic synapses in the rat spinal cord and phosphorylation of GluR1 in response to noxious stimulation revealed with an antigen-unmasking method. J Neurosci 24:5766–5777PubMedGoogle Scholar
  64. 64.
    Polgár E, Watanabe M, Hartmann B, Grant SG, Todd AJ (2008) Expression of AMPA receptor subunits at synapses in laminae I–III of the rodent spinal dorsal horn. Mol Pain 4:5PubMedGoogle Scholar
  65. 65.
    Prybylowski KL, Grossman SD, Wrathall JR, Wolfe BB (2001) Expression of splice variants of the NR1 subunit of the N-methyl-d-aspartate receptor in the normal and injured rat spinal cord. J Neurochem 76:797–805PubMedGoogle Scholar
  66. 66.
    Antal M, Fukazawa Y, Eordogh M, Muszil D, Molnar E, Itakura M, Takahashi M, Shigemoto R (2008) Numbers, densities, and colocalization of AMPA- and NMDA-type glutamate receptors at individual synapses in the superficial spinal dorsal horn of rats. J Neurosci 28:9692–9701PubMedGoogle Scholar
  67. 67.
    Luque JM, Bleuel Z, Malherbe P, Richards JG (1994) Alternatively spliced isoforms of the N-methyl-d-aspartate receptor subunit 1 are differentially distributed within the rat spinal cord. Neuroscience 63:629–635PubMedGoogle Scholar
  68. 68.
    Tölle TR, Berthele A, Laurie DJ, Seeburg PH, Zieglgänsberger W (1995) Cellular and subcellular distribution of NMDAR1 splice variant mRNA in the rat lumbar spinal cord. Eur J NeuroSci 7:1235–1244PubMedGoogle Scholar
  69. 69.
    Popratiloff SA, Weinberg RJ, Rustioni A (1998) NMDAR1 and primary afferent terminals in the superficial spinal cord. NeuroReport 9:2423–2429PubMedGoogle Scholar
  70. 70.
    Aicher SA, Sharma S, Cheng PY, Pickel VM (1997) The N-methyl-d-aspartate (NMDA) receptor is postsynaptic to substance P-containing axon terminals in the rat superficial dorsal horn. Brain Res 772:71–81PubMedGoogle Scholar
  71. 71.
    Momiyama A (2000) Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord. J Physiol 523:621–628PubMedGoogle Scholar
  72. 72.
    Neyton J, Paoletti P (2006) Relating NMDA receptor function to receptor subunit composition: limitations of the pharmacological approach. J Neurosci 26:1331–1333PubMedGoogle Scholar
  73. 73.
    Ye Z, Westlund KN (1996) Ultrastructural localization of glutamate receptor subunits (NMDAR1, AMPA GluR1 and GluR2/3) and spinothalamic tract cells. NeuroReport 7:2581–2585PubMedCrossRefGoogle Scholar
  74. 74.
    Kus L, Saxon D, Beitz AJ (1995) NMDA R1 mRNA distribution in motor and thalamic-projecting sensory neurons in the rat spinal cord and brain stem. Neurosci Lett 196:201–204PubMedGoogle Scholar
  75. 75.
    Hwang SJ, Burette A, Rustioni A, Valtschanoff JG (2004) Vanilloid receptor VR1-positive primary afferents are glutamatergic and contact spinal neurons that co-express neurokinin receptor NK1 and glutamate receptors. J Neurocytol 33:321–329PubMedGoogle Scholar
  76. 76.
    Karlsson U, Sjödin J, Ängeby Möller K, Johansson S, Wikström L, Näsström J (2002) Glutamate-induced currents reveal three functionally distinct NMDA receptor populations in rat dorsal horn—effects of peripheral nerve lesion and inflammation. Neuroscience 112:861–868PubMedGoogle Scholar
  77. 77.
    Tong C-K, Kaftan E, MacDermott A (2008) Functional identification of NR2 subunits contributing to NMDA receptors on substance P receptor-expressing dorsal horn neurons. Mol Pain 4:44PubMedGoogle Scholar
  78. 78.
    Baba H, Doubell TP, Moore KA, Woolf CJ (2000) Silent NMDA receptor-mediated synapses are developmentally regulated in the dorsal horn of the rat spinal cord. J Neurophysiol 83:955–962PubMedGoogle Scholar
  79. 79.
    Larsson M, Broman J (2008) Translocation of GluR1-containing AMPA receptors to a spinal nociceptive synapse during acute noxious stimulation. J Neurosci 28:7084–7090PubMedGoogle Scholar
  80. 80.
    Popratiloff A, Weinberg RJ, Rustioni A (1996) AMPA receptor subunits underlying terminals of fine-caliber primary afferent fibers. J Neurosci 16:3363–3372PubMedGoogle Scholar
  81. 81.
    Todd AJ, Polgár E, Watt C, Bailey MES, and Watanabe M (2009) Neurokinin 1 receptor-expressing projection neurons in laminae III and IV of the rat spinal cord have synaptic AMPA receptors that contain GluR2, GluR3 and GluR4 subunits. Eur J Neurosci 29:718–726Google Scholar
  82. 82.
    Polgár E, Al-Khater KM, Shehab S, Watanabe M, Todd AJ (2008) Large projection neurons in lamina I of the rat spinal cord that lack the neurokinin 1 receptor are densely innervated by VGLUT2-containing axons and possess GluR4-containing AMPA receptors. J Neurosci 28:13150–13160PubMedGoogle Scholar
  83. 83.
    Furuyama T, Kiyama H, Sato K, Park HT, Maeno H, Takagi H, Tohyama M (1993) Region-specific expression of subunits of ionotropic glutamate receptors (AMPA-type, KA-type and NMDA receptors) in the rat spinal cord with special reference to nociception. Brain Res Mol Brain Res 18:141–151PubMedGoogle Scholar
  84. 84.
    Tölle TR, Berthele A, Zieglgänsberger W, Seeburg PH, Wisden W (1993) The differential expression of 16 NMDA and non-NMDA receptor subunits in the rat spinal cord and in periaqueductal gray. J Neurosci 13:5009–5028PubMedGoogle Scholar
  85. 85.
    Stegenga SL, Kalb RG (2001) Developmental regulation of N-methyl-d-aspartate- and kainate-type glutamate receptor expression in the rat spinal cord. Neuroscience 105:499–507PubMedGoogle Scholar
  86. 86.
    Hegarty DM, Mitchell JL, Swanson KC, Aicher SA (2007) Kainate receptors are primarily postsynaptic to SP-containing axon terminals in the trigeminal dorsal horn. Brain Res 1184:149–159PubMedGoogle Scholar
  87. 87.
    Hwang SJ, Pagliardini S, Rustioni A, Valtschanoff JG (2001) Presynaptic kainate receptors in primary afferents to the superficial laminae of the rat spinal cord. J Comp Neurol 436:275–289PubMedGoogle Scholar
  88. 88.
    Lucifora S, Willcockson HH, Lu CR, Darstein M, Phend KD, Valtschanoff JG, Rustioni A (2006) Presynaptic low- and high-affinity kainate receptors in nociceptive spinal afferents. Pain 120:97–105PubMedGoogle Scholar
  89. 89.
    Liu H, Wang H, Sheng M, Jan LY, Jan YN, Basbaum AI (1994) Evidence for presynaptic N-methyl-d-aspartate autoreceptors in the spinal cord dorsal horn. Proc Natl Acad Sci USA 91:8383–8387PubMedGoogle Scholar
  90. 90.
    Lu CR, Hwang SJ, Phend KD, Rustioni A, Valtschanoff JG (2003) Primary afferent terminals that express presynaptic NR1 in rats are mainly from myelinated, mechanosensitive fibers. J Comp Neurol 460:191–202PubMedGoogle Scholar
  91. 91.
    Lu CR, Willcockson HH, Phend KD, Lucifora S, Darstein M, Valtschanoff JG, Rustioni A (2005) Ionotropic glutamate receptors are expressed in GABAergic terminals in the rat superficial dorsal horn. J Comp Neurol 486:169–178PubMedGoogle Scholar
  92. 92.
    O’Donnell R, Molon-Noblot S, Laroque P, Rigby M, Smith D (2004) The ultrastructural localisation of the N-methyl-d-aspartate NR2B receptor subunit in rat lumbar spinal cord. Neurosci Lett 371:24–29PubMedGoogle Scholar
  93. 93.
    Ma QP, Hargreaves RJ (2000) Localization of N-methyl-d-aspartate NR2B subunits on primary sensory neurons that give rise to small-caliber sciatic nerve fibers in rats. Neuroscience 101:699–707PubMedGoogle Scholar
  94. 94.
    Marvizon JC, McRoberts JA, Ennes HS, Song B, Wang X, Jinton L, Corneliussen B, Mayer EA (2002) Two N-methyl-d-aspartate receptors in rat dorsal root ganglia with different subunit composition and localization. J Comp Neurol 446:325–341PubMedGoogle Scholar
  95. 95.
    Sato K, Kiyama H, Park HT, Tohyama M (1993) AMPA, KA and NMDA receptors are expressed in the rat DRG neurones. NeuroReport 4:1263–1265PubMedGoogle Scholar
  96. 96.
    McRoberts JA, Coutinho SV, Marvizon JC, Grady EF, Tognetto M, Sengupta JN, Ennes HS, Chaban VV, Amadesi S, Creminon C, Lanthorn T, Geppetti P, Bunnett NW, Mayer EA (2001) Role of peripheral N-methyl-d-aspartate (NMDA) receptors in visceral nociception in rats. Gastroenterology 120:1737–1748PubMedGoogle Scholar
  97. 97.
    Hummel M, Strassle B, Miller S, Kaftan E, Whiteside G (2008) Anatomical localization and expression pattern for the NMDA-2D receptor subunit in a rat model of neuropathic pain. Neuroscience 155:492–502PubMedGoogle Scholar
  98. 98.
    Shigemoto R, Ohishi H, Nakanishi S, Mizuno N (1992) Expression of the mRNA for the rat NMDA receptor (NMDAR1) in the sensory and autonomic ganglion neurons. Neurosci Lett 144:229–232PubMedGoogle Scholar
  99. 99.
    Willcockson H, Valtschanoff J (2008) AMPA and NMDA glutamate receptors are found in both peptidergic and non-peptidergic primary afferent neurons in the rat. Cell Tissue Res 334:17–23PubMedGoogle Scholar
  100. 100.
    Lu CR, Hwang SJ, Phend KD, Rustioni A, Valtschanoff JG (2002) Primary afferent terminals in spinal cord express presynaptic AMPA receptors. J Neurosci 22:9522–9529PubMedGoogle Scholar
  101. 101.
    Lee CJ, Kong H, Manzini MC, Albuquerque C, Chao MV, MacDermott AB (2001) Kainate receptors expressed by a subpopulation of developing nociceptors rapidly switch from high to low Ca2+ permeability. J Neurosci 21:4572–4581PubMedGoogle Scholar
  102. 102.
    Lu Y, Perl ER (2003) A specific inhibitory pathway between substantia gelatinosa neurons receiving direct C-fiber input. J Neurosci 23:8752–8758PubMedGoogle Scholar
  103. 103.
    Santos SF, Rebelo S, Derkach VA, Safronov BV (2007) Excitatory interneurons dominate sensory processing in the spinal substantia gelatinosa of rat. J Physiol 581:241–254PubMedGoogle Scholar
  104. 104.
    Dahlhaus A, Ruscheweyh R, Sandkühler J (2005) Synaptic input of rat spinal lamina I projection and unidentified neurones in vitro. J Physiol 566:355–368PubMedGoogle Scholar
  105. 105.
    Tong CK, MacDermott AB (2006) Both Ca2+-permeable and -impermeable AMPA receptors contribute to primary synaptic drive onto rat dorsal horn neurons. J Physiol 575:133–144PubMedGoogle Scholar
  106. 106.
    Yoshimura M, Nishi S (1993) Blind patch-clamp recordings from substantia gelatinosa neurons in adult rat spinal cord slices: pharmacological properties of synaptic currents. Neuroscience 53:519–526PubMedGoogle Scholar
  107. 107.
    Vikman KS, Rycroft BK, Christie MJ (2008) Switch to Ca2+-permeable AMPA and reduced NR2B NMDA receptor-mediated neurotransmission at dorsal horn nociceptive synapses during inflammatory pain in the rat. J Physiol 586:515–527PubMedGoogle Scholar
  108. 108.
    Youn DH, Randić M (2004) Modulation of excitatory synaptic transmission in the spinal substantia gelatinosa of mice deficient in the kainate receptor GluR5 and/or GluR6 subunit. J Physiol 555:683–698PubMedGoogle Scholar
  109. 109.
    Kerchner GA, Wilding TJ, Li P, Zhuo M, Huettner JE (2001) Presynaptic kainate receptors regulate spinal sensory transmission. J Neurosci 21:59–66PubMedGoogle Scholar
  110. 110.
    Li P, Wilding TJ, Kim SJ, Calejesan AA, Huettner JE, Zhuo M (1999) Kainate-receptor-mediated sensory synaptic transmission in mammalian spinal cord. Nature 397:161–164PubMedGoogle Scholar
  111. 111.
    Youn DH, Voitenko N, Gerber G, Park YK, Galik J, Randić M (2005) Altered long-term synaptic plasticity and kainate-induced Ca2+ transients in the substantia gelatinosa neurons in GLU(K6)-deficient mice. Brain Res Mol Brain Res 142:9–18PubMedGoogle Scholar
  112. 112.
    Engelman HS, Allen TB, MacDermott AB (1999) The distribution of neurons expressing calcium-permeable AMPA receptors in the superficial laminae of the spinal cord dorsal horn. J Neurosci 19:2081–2089PubMedGoogle Scholar
  113. 113.
    Hartmann B, Ahmadi S, Heppenstall PA, Lewin GR, Schott C, Borchardt T, Seeburg PH, Zeilhofer HU, Sprengel R, Kuner R (2004) The AMPA receptor subunits GluR-A and GluR-B reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron 44:637–650PubMedGoogle Scholar
  114. 114.
    Katano T, Furue H, Okuda-Ashitaka E, Tagaya M, Watanabe M, Yoshimura M, Ito S (2008) N-ethylmaleimide-sensitive fusion protein (NSF) is involved in central sensitization in the spinal cord through GluR2 subunit composition switch after inflammation. Eur J NeuroSci 27:3161–3170PubMedGoogle Scholar
  115. 115.
    Torsney C, MacDermott AB (2006) Disinhibition opens the gate to pathological pain signaling in superficial neurokinin 1 receptor-expressing neurons in rat spinal cord. J Neurosci 26:1833–1843PubMedGoogle Scholar
  116. 116.
    Baba H, Ji RR, Kohno T, Moore KA, Ataka T, Wakai A, Okamoto M, Woolf CJ (2003) Removal of GABAergic inhibition facilitates polysynaptic A fiber-mediated excitatory transmission to the superficial spinal dorsal horn. Mol Cell Neurosci 24:818–830PubMedGoogle Scholar
  117. 117.
    Budai D, Larson AA (1994) GYKI 52466 inhibits AMPA/kainate and peripheral mechanical sensory activity. NeuroReport 5:881–884PubMedGoogle Scholar
  118. 118.
    Dougherty PM, Palecek J, Paleckova V, Sorkin LS, Willis WD (1992) The role of NMDA and non-NMDA excitatory amino acid receptors in the excitation of primate spinothalamic tract neurons by mechanical, chemical, thermal, and electrical stimuli. J Neurosci 12:3025–3041PubMedGoogle Scholar
  119. 119.
    Neugebauer V, Lucke T, Schaible HG (1993) Differential effects of N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists on the responses of rat spinal neurons with joint input. Neurosci Lett 155:29–32PubMedGoogle Scholar
  120. 120.
    Schneider SP, Perl ER (1994) Synaptic mediation from cutaneous mechanical nociceptors. J Neurophysiol 72:612–621PubMedGoogle Scholar
  121. 121.
    King AE, Lopez-Garcia JA (1993) Excitatory amino acid receptor-mediated neurotransmission from cutaneous afferents in rat dorsal horn in vitro. J Physiol 472:443–457PubMedGoogle Scholar
  122. 122.
    Furue H, Narikawa K, Kumamoto E, Yoshimura M (1999) Responsiveness of rat substantia gelatinosa neurones to mechanical but not thermal stimuli revealed by in vivo patch-clamp recording. J Physiol 521(Pt 2):529–535PubMedGoogle Scholar
  123. 123.
    Headley PM, Parsons CG, West DC (1987) The role of N-methylaspartate receptors in mediating responses of rat and cat spinal neurones to defined sensory stimuli. J Physiol 385:169–188PubMedGoogle Scholar
  124. 124.
    Chizh BA, Cumberbatch MJ, Herrero JF, Stirk GC, Headley PM (1997) Stimulus intensity, cell excitation and the N-methyl-d-aspartate receptor component of sensory responses in the rat spinal cord in vivo. Neuroscience 80:251–265PubMedGoogle Scholar
  125. 125.
    Palecek J, Neugebauer V, Carlton SM, Iyengar S, Willis WD (2004) The effect of a kainate GluR5 receptor antagonist on responses of spinothalamic tract neurons in a model of peripheral neuropathy in primates. Pain 111:151–161PubMedGoogle Scholar
  126. 126.
    Kong LL, Yu LC (2006) It is AMPA receptor, not kainate receptor, that contributes to the NBQX-induced antinociception in the spinal cord of rats. Brain Res 1100:73–77PubMedGoogle Scholar
  127. 127.
    Lutfy K, Cai SX, Woodward RM, Weber E (1997) Antinociceptive effects of NMDA and non-NMDA receptor antagonists in the tail flick test in mice. Pain 70:31–40PubMedGoogle Scholar
  128. 128.
    Näsström J, Karlsson U, Post C (1992) Antinociceptive actions of different classes of excitatory amino acid receptor antagonists in mice. Eur J Pharmacol 212:21–29PubMedGoogle Scholar
  129. 129.
    Yoshimura M, Yonehara N (2006) Alteration in sensitivity of ionotropic glutamate receptors and tachykinin receptors in spinal cord contribute to development and maintenance of nerve injury-evoked neuropathic pain. Neurosci Res 56:21–28PubMedGoogle Scholar
  130. 130.
    Guo W, Zou S, Tal M, Ren K (2002) Activation of spinal kainate receptors after inflammation: behavioral hyperalgesia and subunit gene expression. Eur J Pharmacol 452:309–318PubMedGoogle Scholar
  131. 131.
    Advokat C, Rutherford D (1995) Selective antinociceptive effect of excitatory amino acid antagonists in intact and acute spinal rats. Pharmacol Biochem Behav 51:855–860PubMedGoogle Scholar
  132. 132.
    Nishiyama T, Gyermek L, Lee C, Kawasaki-Yatsugi S, Yamaguchi T (1999) The spinal antinociceptive effects of a novel competitive AMPA receptor antagonist, YM872, on thermal or formalin-induced pain in rats. Anesth Analg 89:143–147PubMedGoogle Scholar
  133. 133.
    Coderre TJ, Van Empel I (1994) The utility of excitatory amino acid (EAA) antagonists as analgesic agents. II. Assessment of the antinociceptive activity of combinations of competitive and non-competitive NMDA antagonists with agents acting at allosteric-glycine and polyamine receptor sites. Pain 59:353–359PubMedGoogle Scholar
  134. 134.
    Ren K, Williams GM, Hylden JL, Ruda MA, Dubner R (1992) The intrathecal administration of excitatory amino acid receptor antagonists selectively attenuated carrageenan-induced behavioral hyperalgesia in rats. Eur J Pharmacol 219:235–243PubMedGoogle Scholar
  135. 135.
    Kontinen VK, Meert TF (2002) Vocalization responses after intrathecal administration of ionotropic glutamate receptor agonists in rats. Anesth Analg 95:997–1001 table of contentsPubMedGoogle Scholar
  136. 136.
    Sorkin LS, Yaksh TL, Doom CM (2001) Pain models display differential sensitivity to Ca2+-permeable non-NMDA glutamate receptor antagonists. Anesthesiology 95:965–973PubMedGoogle Scholar
  137. 137.
    Garraway SM, Xu Q, Inturrisi CE (2007) Design and evaluation of small interfering RNAs that target expression of the N-methyl-d-aspartate receptor NR1 subunit gene in the spinal cord dorsal horn. J Pharmacol Exp Ther 322:982–988PubMedGoogle Scholar
  138. 138.
    Shimoyama N, Shimoyama M, Davis AM, Monaghan DT, Inturrisi CE (2005) An antisense oligonucleotide to the N-methyl-d-aspartate (NMDA) subunit NMDAR1 attenuates NMDA-induced nociception, hyperalgesia, and morphine tolerance. J Pharmacol Exp Ther 312:834–840PubMedGoogle Scholar
  139. 139.
    South SM, Kohno T, Kaspar BK, Hegarty D, Vissel B, Drake CT, Ohata M, Jenab S, Sailer AW, Malkmus S, Masuyama T, Horner P, Bogulavsky J, Gage FH, Yaksh TL, Woolf CJ, Heinemann SF, Inturrisi CE (2003) A conditional deletion of the NR1 subunit of the NMDA receptor in adult spinal cord dorsal horn reduces NMDA currents and injury-induced pain. J Neurosci 23:5031–5040PubMedGoogle Scholar
  140. 140.
    Garraway SM, Xu Q, Inturrisi CE (2009) siRNA-mediated knockdown of the NR1 subunit gene of the NMDA receptor attenuates formalin-induced pain behaviors in adult rats. J Pain 10:380–390PubMedGoogle Scholar
  141. 141.
    Dickenson AH, Chapman V, Green GM (1997) The pharmacology of excitatory and inhibitory amino acid-mediated events in the transmission and modulation of pain in the spinal cord. Gen Pharmacol 28:633–638PubMedGoogle Scholar
  142. 142.
    Hama A, Woon Lee J, Sagen J (2003) Differential efficacy of intrathecal NMDA receptor antagonists on inflammatory mechanical and thermal hyperalgesia in rats. Eur J Pharmacol 459:49–58PubMedGoogle Scholar
  143. 143.
    Tan PH, Yang LC, Shih HC, Lan KC, Cheng JT (2005) Gene knockdown with intrathecal siRNA of NMDA receptor NR2B subunit reduces formalin-induced nociception in the rat. Gene Ther 12:59–66PubMedGoogle Scholar
  144. 144.
    Qu XX, Cai J, Li MJ, Chi YN, Liao FF, Liu FY, Wan Y, Han JS, Xing GG (2009) Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain. Exp Neurol 215:298–307PubMedGoogle Scholar
  145. 145.
    Malmberg AB, Gilbert H, McCabe RT, Basbaum AI (2003) Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T. Pain 101:109–116PubMedGoogle Scholar
  146. 146.
    Hama A, Sagen J (2009) Antinociceptive effects of the marine snail peptides conantokin-G and conotoxin MVIIA alone and in combination in rat models of pain. Neuropharmacology 56:556–563PubMedGoogle Scholar
  147. 147.
    Hizue M, Pang CH, Yokoyama M (2005) Involvement of N-methyl-d-aspartate-type glutamate receptor ε1 and ε4 subunits in tonic inflammatory pain and neuropathic pain. NeuroReport 16:1667–1670PubMedGoogle Scholar
  148. 148.
    Petrenko AB, Yamakura T, Baba H, Sakimura K (2003) Unaltered pain-related behavior in mice lacking NMDA receptor GluRε1 subunit. Neurosci Res 46:199–204PubMedGoogle Scholar
  149. 149.
    Mascias P, Scheede M, Bloms-Funke P, Chizh B (2002) Modulation of spinal nociception by GluR5 kainate receptor ligands in acute and hyperalgesic states and the role of gabaergic mechanisms. Neuropharmacology 43:327–339PubMedGoogle Scholar
  150. 150.
    Wu DC, Zhou N, Yu LC (2003) Anti-nociceptive effect induced by intrathecal injection of ATPA, an effect enhanced and prolonged by concanavalin A. Brain Res 959:275–279PubMedGoogle Scholar
  151. 151.
    Ko S, Zhao MG, Toyoda H, Qiu CS, Zhuo M (2005) Altered behavioral responses to noxious stimuli and fear in glutamate receptor 5 (GluR5)- or GluR6-deficient mice. J Neurosci 25:977–984PubMedGoogle Scholar
  152. 152.
    Herrero JF, Laird JM, Lopez-Garcia JA (2000) Wind-up of spinal cord neurones and pain sensation: much ado about something? Prog Neurobiol 61:169–203PubMedGoogle Scholar
  153. 153.
    Li J, Simone DA, Larson AA (1999) Windup leads to characteristics of central sensitization. Pain 79:75–82PubMedGoogle Scholar
  154. 154.
    Woolf CJ (1996) Windup and central sensitization are not equivalent. Pain 66:105–108PubMedGoogle Scholar
  155. 155.
    Dickenson AH, Sullivan AF (1990) Differential effects of excitatory amino acid antagonists on dorsal horn nociceptive neurones in the rat. Brain Res 506:31–39PubMedGoogle Scholar
  156. 156.
    Svendsen F, Rygh LJ, Hole K, Tjølsen A (1999) Dorsal horn NMDA receptor function is changed after peripheral inflammation. Pain 83:517–523PubMedGoogle Scholar
  157. 157.
    Woda A, Blanc O, Voisin DL, Coste J, Molat JL, Luccarini P (2004) Bidirectional modulation of windup by NMDA receptors in the rat spinal trigeminal nucleus. Eur J NeuroSci 19:2009–2016PubMedGoogle Scholar
  158. 158.
    Kalliomäki J, Granmo M, Schouenborg J (2003) Spinal NMDA-receptor dependent amplification of nociceptive transmission to rat primary somatosensory cortex (SI). Pain 104:195–200PubMedGoogle Scholar
  159. 159.
    Stanfa LC, Dickenson AH (1999) The role of non-N-methyl-d-aspartate ionotropic glutamate receptors in the spinal transmission of nociception in normal animals and animals with carrageenan inflammation. Neuroscience 93:1391–1398PubMedGoogle Scholar
  160. 160.
    Morisset V, Nagy F (2000) Plateau potential-dependent windup of the response to primary afferent stimuli in rat dorsal horn neurons. Eur J NeuroSci 12:3087–3095PubMedGoogle Scholar
  161. 161.
    Russo RE, Hounsgaard J (1994) Short-term plasticity in turtle dorsal horn neurons mediated by L-type Ca2+ channels. Neuroscience 61:191–197PubMedGoogle Scholar
  162. 162.
    Fossat P, Sibon I, Le Masson G, Landry M, Nagy F (2007) L-type calcium channels and NMDA receptors: a determinant duo for short-term nociceptive plasticity. Eur J NeuroSci 25:127–135PubMedGoogle Scholar
  163. 163.
    Liu H, Mantyh PW, Basbaum AI (1997) NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386:721–724PubMedGoogle Scholar
  164. 164.
    Nazarian A, Gu G, Gracias NG, Wilkinson K, Hua XY, Vasko MR, Yaksh TL (2008) Spinal N-methyl-d-aspartate receptors and nociception-evoked release of primary afferent substance P. Neuroscience 152:119–127PubMedGoogle Scholar
  165. 165.
    Bardoni R, Torsney C, Tong CK, Prandini M, MacDermott AB (2004) Presynaptic NMDA receptors modulate glutamate release from primary sensory neurons in rat spinal cord dorsal horn. J Neurosci 24:2774–2781PubMedGoogle Scholar
  166. 166.
    Lee C, Bardoni R, Tong C, Engelman H, Joseph D, Magherini P, MacDermott A (2002) Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release. Neuron 35:135–146PubMedGoogle Scholar
  167. 167.
    Rozas JL, Paternain AV, Lerma J (2003) Noncanonical signaling by ionotropic kainate receptors. Neuron 39:543–553PubMedGoogle Scholar
  168. 168.
    Kerchner GA, Wang GD, Qiu CS, Huettner JE, Zhuo M (2001) Direct presynaptic regulation of GABA/glycine release by kainate receptors in the dorsal horn: an ionotropic mechanism. Neuron 32:477–488PubMedGoogle Scholar
  169. 169.
    Xu H, Wu LJ, Zhao MG, Toyoda H, Vadakkan KI, Jia Y, Pinaud R, Zhuo M (2006) Presynaptic regulation of the inhibitory transmission by GluR5-containing kainate receptors in spinal substantia gelatinosa. Mol Pain 2:29PubMedGoogle Scholar
  170. 170.
    Engelman HS, Anderson RL, Daniele C, Macdermott AB (2006) Presynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors modulate release of inhibitory amino acids in rat spinal cord dorsal horn. Neuroscience 139:539–553PubMedGoogle Scholar
  171. 171.
    Woolf CJ (1983) Evidence for a central component of post-injury pain hypersensitivity. Nature 306:686–688PubMedGoogle Scholar
  172. 172.
    Sandkühler J (2009) Models and mechanisms of hyperalgesia and allodynia. Physiol Rev 89:707–758PubMedGoogle Scholar
  173. 173.
    Randić M, Jiang MC, Cerne R (1993) Long-term potentiation and long-term depression of primary afferent neurotransmission in the rat spinal cord. J Neurosci 13:5228–5241PubMedGoogle Scholar
  174. 174.
    Ji RR, Kohno T, Moore KA, Woolf CJ (2003) Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci 26:696–705PubMedGoogle Scholar
  175. 175.
    Sandkühler J (2000) Learning and memory in pain pathways. Pain 88:113–118PubMedGoogle Scholar
  176. 176.
    Sandkühler J (2007) Understanding LTP in pain pathways. Mol Pain 3:9PubMedGoogle Scholar
  177. 177.
    Willis WD (2002) Long-term potentiation in spinothalamic neurons. Brain Res Brain Res Rev 40:202–214PubMedGoogle Scholar
  178. 178.
    Ikeda H, Stark J, Fischer H, Wagner M, Drdla R, Jager T, Sandkühler J (2006) Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science 312:1659–1662PubMedGoogle Scholar
  179. 179.
    Klein T, Magerl W, Hopf HC, Sandkühler J, Treede RD (2004) Perceptual correlates of nociceptive long-term potentiation and long-term depression in humans. J Neurosci 24:964–971PubMedGoogle Scholar
  180. 180.
    Klein T, Magerl W, Nickel U, Hopf HC, Sandkühler J, Treede RD (2007) Effects of the NMDA-receptor antagonist ketamine on perceptual correlates of long-term potentiation within the nociceptive system. Neuropharmacology 52:655–661PubMedGoogle Scholar
  181. 181.
    Drdla R, Sandkühler J (2008) Long-term potentiation at C-fibre synapses by low-level presynaptic activity in vivo. Mol Pain 4:18PubMedGoogle Scholar
  182. 182.
    Liu X, Sandkühler J (1997) Characterization of long-term potentiation of C-fiber-evoked potentials in spinal dorsal horn of adult rat: essential role of NK1 and NK2 receptors. J Neurophysiol 78:1973–1982PubMedGoogle Scholar
  183. 183.
    Jung SJ, Kim SJ, Park YK, Oh SB, Cho K, Kim J (2006) Group I mGluR regulates the polarity of spike-timing dependent plasticity in substantia gelatinosa neurons. Biochem Biophys Res Commun 347:509–516PubMedGoogle Scholar
  184. 184.
    Ikeda H, Murase K (2004) Glial nitric oxide-mediated long-term presynaptic facilitation revealed by optical imaging in rat spinal dorsal horn. J Neurosci 24:9888–9896PubMedGoogle Scholar
  185. 185.
    Schouenborg J (1984) Functional and topographical properties of field potentials evoked in rat dorsal horn by cutaneous C-fibre stimulation. J Physiol 356:169–192PubMedGoogle Scholar
  186. 186.
    Haugan F, Wibrand K, Fiskå A, Bramham CR, Tjølsen A (2008) Stability of long term facilitation and expression of zif268 and Arc in the spinal cord dorsal horn is modulated by conditioning stimulation within the physiological frequency range of primary afferent fibers. Neuroscience 154:1568–1575PubMedGoogle Scholar
  187. 187.
    Todd AJ, Puskar Z, Spike RC, Hughes C, Watt C, Forrest L (2002) Projection neurons in lamina I of rat spinal cord with the neurokinin 1 receptor are selectively innervated by substance p-containing afferents and respond to noxious stimulation. J Neurosci 22:4103–4113PubMedGoogle Scholar
  188. 188.
    Liu XG, Sandkühler J (1995) Long-term potentiation of C-fiber-evoked potentials in the rat spinal dorsal horn is prevented by spinal N-methyl-d-aspartic acid receptor blockage. Neurosci Lett 191:43–46PubMedGoogle Scholar
  189. 189.
    Liu W-T, Han Y, Li H-C, Adams B, Zheng J-H, Wu Y-P, Henkemeyer M, Song X-J (2009) An in vivo mouse model of long-term potentiation at synapses between primary afferent C-fibers and spinal dorsal horn neurons: essential role of EphB1 receptor. Mol Pain 5:29PubMedGoogle Scholar
  190. 190.
    Ikeda H, Heinke B, Ruscheweyh R, Sandkühler J (2003) Synaptic plasticity in spinal lamina I projection neurons that mediate hyperalgesia. Science 299:1237–1240PubMedGoogle Scholar
  191. 191.
    Hamba M, Onodera K, Takahashi T (2000) Long-term potentiation of primary afferent neurotransmission at trigeminal synapses of juvenile rats. Eur J NeuroSci 12:1128–1134PubMedGoogle Scholar
  192. 192.
    Liang YC, Huang CC, Hsu KS (2005) Characterization of long-term potentiation of primary afferent transmission at trigeminal synapses of juvenile rats: essential role of subtype 5 metabotropic glutamate receptors. Pain 114:417–428PubMedGoogle Scholar
  193. 193.
    Liu XG, Sandkühler J (1998) Activation of spinal N-methyl-d-aspartate or neurokinin receptors induces long-term potentiation of spinal C-fibre-evoked potentials. Neuroscience 86:1209–1216PubMedGoogle Scholar
  194. 194.
    Liu XG, Morton CR, Azkue JJ, Zimmermann M, Sandkühler J (1998) Long-term depression of C-fibre-evoked spinal field potentials by stimulation of primary afferent Aδ-fibres in the adult rat. Eur J NeuroSci 10:3069–3075PubMedGoogle Scholar
  195. 195.
    Sandkühler J, Chen JG, Cheng G, Randić M (1997) Low-frequency stimulation of afferent Aδ-fibers induces long-term depression at primary afferent synapses with substantia gelatinosa neurons in the rat. J Neurosci 17:6483–6491PubMedGoogle Scholar
  196. 196.
    Gu JG, Albuquerque C, Lee CJ, MacDermott AB (1996) Synaptic strengthening through activation of Ca2+-permeable AMPA receptors. Nature 381:793–796PubMedGoogle Scholar
  197. 197.
    Youn DH, Royle G, Kolaj M, Vissel B, Randić M (2008) Enhanced LTP of primary afferent neurotransmission in AMPA receptor GluR2-deficient mice. Pain 136:158–167PubMedGoogle Scholar
  198. 198.
    Azkue JJ, Liu XG, Zimmermann M, Sandkühler J (2003) Induction of long-term potentiation of C fibre-evoked spinal field potentials requires recruitment of group I, but not group II/III metabotropic glutamate receptors. Pain 106:373–379PubMedGoogle Scholar
  199. 199.
    Zhong J, Gerber G, Kojic L, Randić M (2000) Dual modulation of excitatory synaptic transmission by agonists at group I metabotropic glutamate receptors in the rat spinal dorsal horn. Brain Res 887:359–377PubMedGoogle Scholar
  200. 200.
    Song XJ, Zheng JH, Cao JL, Liu WT, Song XS, Huang ZJ (2008) EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats. Pain 139:168–180PubMedGoogle Scholar
  201. 201.
    Zhou LJ, Zhong Y, Ren WJ, Li YY, Zhang T, Liu XG (2008) BDNF induces late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. Exp Neurol 212:507–514PubMedGoogle Scholar
  202. 202.
    Zhang XC, Zhang YQ, Zhao ZQ (2006) Different roles of two nitric oxide activated pathways in spinal long-term potentiation of C-fiber-evoked field potentials. Neuropharmacology 50:748–754PubMedGoogle Scholar
  203. 203.
    Reymann KG, Frey JU (2007) The late maintenance of hippocampal LTP: requirements, phases, ‘synaptic tagging’, ‘late-associativity’ and implications. Neuropharmacology 52:24–40PubMedGoogle Scholar
  204. 204.
    Hu NW, Zhang HM, Hu XD, Li MT, Zhang T, Zhou LJ, Liu XG (2003) Protein synthesis inhibition blocks the late-phase LTP of C-fiber evoked field potentials in rat spinal dorsal horn. J Neurophysiol 89:2354–2359PubMedGoogle Scholar
  205. 205.
    Lisman J, Schulman H, Cline H (2002) The molecular basis of CaMKII function in synaptic and behavioural memory. Nat Rev Neurosci 3:175–190PubMedGoogle Scholar
  206. 206.
    Yang HW, Hu XD, Zhang HM, Xin WJ, Li MT, Zhang T, Zhou LJ, Liu XG (2004) Roles of CaMKII, PKA, and PKC in the induction and maintenance of LTP of C-fiber-evoked field potentials in rat spinal dorsal horn. J Neurophysiol 91:1122–1133PubMedGoogle Scholar
  207. 207.
    Lisman JE, Zhabotinsky AM (2001) A model of synaptic memory: a CaMKII/PP1 switch that potentiates transmission by organizing an AMPA receptor anchoring assembly. Neuron 31:191–201PubMedGoogle Scholar
  208. 208.
    Miller P, Zhabotinsky AM, Lisman JE, Wang XJ (2005) The stability of a stochastic CaMKII switch: dependence on the number of enzyme molecules and protein turnover. PLoS Biol 3:e107PubMedGoogle Scholar
  209. 209.
    Mullasseril P, Dosemeci A, Lisman JE, Griffith LC (2007) A structural mechanism for maintaining the ‘on-state’ of the CaMKII memory switch in the post-synaptic density. J Neurochem 103:357–364PubMedGoogle Scholar
  210. 210.
    Chen HX, Otmakhov N, Strack S, Colbran RJ, Lisman JE (2001) Is persistent activity of calcium/calmodulin-dependent kinase required for the maintenance of LTP? J Neurophysiol 85:1368–1376PubMedGoogle Scholar
  211. 211.
    Sanhueza M, McIntyre CC, Lisman JE (2007) Reversal of synaptic memory by Ca2+/calmodulin-dependent protein kinase II inhibitor. J Neurosci 27:5190–5199PubMedGoogle Scholar
  212. 212.
    Gerber U, Gee CE, Benquet P (2007) Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol 7:56–61PubMedGoogle Scholar
  213. 213.
    Khawaja AM, Rogers DF (1996) Tachykinins: receptor to effector. Int J Biochem Cell Biol 28:721–738PubMedGoogle Scholar
  214. 214.
    Chen J, Heinke B, Sandkühler J (2000) Activation of group I metabotropic glutamate receptors induces long-term depression at sensory synapses in superficial spinal dorsal horn. Neuropharmacology 39:2231–2243PubMedGoogle Scholar
  215. 215.
    Cheng G, Randić M (2003) Involvement of intracellular calcium and protein phosphatases in long-term depression of A-fiber-mediated primary afferent neurotransmission. Brain Res Dev Brain Res 144:73–82PubMedGoogle Scholar
  216. 216.
    Nishimura W, Muratani T, Tatsumi S, Sakimura K, Mishina M, Minami T, Ito S (2004) Characterization of N-methyl-d-aspartate receptor subunits responsible for postoperative pain. Eur J Pharmacol 503:71–75PubMedGoogle Scholar
  217. 217.
    Nozaki-Taguchi N, Yaksh TL (2002) Pharmacology of spinal glutamatergic receptors in post-thermal injury-evoked tactile allodynia and thermal hyperalgesia. Anesthesiology 96:617–626PubMedGoogle Scholar
  218. 218.
    Pogatzki EM, Zahn PK, Brennan TJ (2000) Effect of pretreatment with intrathecal excitatory amino acid receptor antagonists on the development of pain behavior caused by plantar incision. Anesthesiology 93:489–496PubMedGoogle Scholar
  219. 219.
    Yukhananov R, Guan J, Crosby G (2002) Antisense oligonucleotides to N-methyl-d-aspartate receptor subunits attenuate formalin-induced nociception in the rat. Brain Res 930:163–169PubMedGoogle Scholar
  220. 220.
    Jones TL, Sorkin LS (2004) Calcium-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate receptors mediate development, but not maintenance, of secondary allodynia evoked by first-degree burn in the rat. J Pharmacol Exp Ther 310:223–229PubMedGoogle Scholar
  221. 221.
    Sorkin LS, Yaksh TL, Doom CM (1999) Mechanical allodynia in rats is blocked by a Ca2+ permeable AMPA receptor antagonist. NeuroReport 10:3523–3526PubMedGoogle Scholar
  222. 222.
    Turner MS, Hamamoto DT, Hodges JS, Maccecchini ML, Simone DA (2003) SYM 2081, an agonist that desensitizes kainate receptors, attenuates capsaicin and inflammatory hyperalgesia. Brain Res 973:252–264PubMedGoogle Scholar
  223. 223.
    Garry EM, Moss A, Delaney A, O’Neill F, Blakemore J, Bowen J, Husi H, Mitchell R, Grant SG, Fleetwood-Walker SM (2003) Neuropathic sensitization of behavioral reflexes and spinal NMDA receptor/CaM kinase II interactions are disrupted in PSD-95 mutant mice. Curr Biol 13:321–328PubMedGoogle Scholar
  224. 224.
    Jones TL, Lustig AC, Sorkin LS (2007) Secondary hyperalgesia in the postoperative pain model is dependent on spinal calcium/calmodulin-dependent protein kinase IIα activation. Anesth Analg 105:1650–1656PubMedGoogle Scholar
  225. 225.
    Jones TL, Sorkin LS (2005) Activated PKA and PKC, but not CaMKIIα, are required for AMPA/Kainate-mediated pain behavior in the thermal stimulus model. Pain 117:259–270PubMedGoogle Scholar
  226. 226.
    Liu XJ, Gingrich JR, Vargas-Caballero M, Dong YN, Sengar A, Beggs S, Wang SH, Ding HK, Frankland PW, Salter MW (2008) Treatment of inflammatory and neuropathic pain by uncoupling Src from the NMDA receptor complex. Nat Med 14:1325–1332PubMedGoogle Scholar
  227. 227.
    Luo F, Yang C, Chen Y, Shukla P, Tang L, Wang LX, Wang ZJ (2008) Reversal of chronic inflammatory pain by acute inhibition of Ca2+/calmodulin-dependent protein kinase II. J Pharmacol Exp Ther. 325:267–275PubMedGoogle Scholar
  228. 228.
    Velázquez KT, Mohammad H, Sweitzer SM (2007) Protein kinase C in pain: involvement of multiple isoforms. Pharmacol Res 55:578–589PubMedGoogle Scholar
  229. 229.
    Xu Q, Garraway SM, Weyerbacher AR, Shin SJ, Inturrisi CE (2008) Activation of the neuronal extracellular signal-regulated kinase 2 in the spinal cord dorsal horn is required for Complete Freund’s adjuvant-induced pain hypersensitivity. J Neurosci 28:14087–14096PubMedGoogle Scholar
  230. 230.
    Fang L, Wu J, Lin Q, Willis WD (2002) Calcium-calmodulin-dependent protein kinase II contributes to spinal cord central sensitization. J Neurosci 22:4196–4204PubMedGoogle Scholar
  231. 231.
    Larsson M, Broman J (2006) Pathway-specific bidirectional regulation of Ca2+/calmodulin-dependent protein kinase II at spinal nociceptive synapses after acute noxious stimulation. J Neurosci 26:4198–4205PubMedGoogle Scholar
  232. 232.
    Chen Y, Luo F, Yang C, Kirkmire C, and Wang ZJ (2009) Acute inhibition of Ca2+/calmodulin-dependent protein kinase II reverses experimental neuropathic pain in mice. J Pharmacol Exp Ther 330:650–659Google Scholar
  233. 233.
    Galan A, Laird JM, Cervero F (2004) In vivo recruitment by painful stimuli of AMPA receptor subunits to the plasma membrane of spinal cord neurons. Pain 112:315–323PubMedGoogle Scholar
  234. 234.
    Dai Y, Wang H, Ogawa A, Yamanaka H, Obata K, Tokunaga A, Noguchi K (2005) Ca2+/calmodulin-dependent protein kinase II in the spinal cord contributes to neuropathic pain in a rat model of mononeuropathy. Eur J NeuroSci 21:2467–2474PubMedGoogle Scholar
  235. 235.
    Choi SS, Seo YJ, Shim EJ, Kwon MS, Lee JY, Ham YO, Suh HW (2006) Involvement of phosphorylated Ca2+/calmodulin-dependent protein kinase II and phosphorylated extracellular signal-regulated protein in the mouse formalin pain model. Brain Res 1108:28–38PubMedGoogle Scholar
  236. 236.
    Zeitz KP, Giese KP, Silva AJ, Basbaum AI (2004) The contribution of autophosphorylated α-calcium-calmodulin kinase II to injury-induced persistent pain. Neuroscience 128:889–898PubMedGoogle Scholar
  237. 237.
    Otmakhov N, Tao-Cheng JH, Carpenter S, Asrican B, Dosemeci A, Reese TS, Lisman J (2004) Persistent accumulation of calcium/calmodulin-dependent protein kinase II in dendritic spines after induction of NMDA receptor-dependent chemical long-term potentiation. J Neurosci 24:9324–9331PubMedGoogle Scholar
  238. 238.
    Zhang YP, Holbro N, Oertner TG (2008) Optical induction of plasticity at single synapses reveals input-specific accumulation of alphaCaMKII. Proc Natl Acad Sci USA 105:12039–12044PubMedGoogle Scholar
  239. 239.
    Merrill MA, Chen Y, Strack S, Hell JW (2005) Activity-driven postsynaptic translocation of CaMKII. Trends Pharmacol Sci 26:645–653PubMedGoogle Scholar
  240. 240.
    Lee S-JR, Escobedo-Lozoya Y, Szatmari EM, Yasuda R (2009) Activation of CaMKII in single dendritic spines during long-term potentiation. Nature 458:299–304PubMedGoogle Scholar
  241. 241.
    Larsson M, Broman J (2005) Different basal levels of CaMKII phosphorylated at Thr286/287 at nociceptive and low-threshold primary afferent synapses. Eur J NeuroSci 21:2445–2458PubMedGoogle Scholar
  242. 242.
    Zahn PK, Brennan TJ (1998) Lack of effect of intrathecally administered N-methyl-d-aspartate receptor antagonists in a rat model for postoperative pain. Anesthesiology 88:143–156PubMedGoogle Scholar
  243. 243.
    Zahn PK, Pogatzki-Zahn EM, Brennan TJ (2005) Spinal administration of MK-801 and NBQX demonstrates NMDA-independent dorsal horn sensitization in incisional pain. Pain 114:499–510PubMedGoogle Scholar
  244. 244.
    Brenner GJ, Ji RR, Shaffer S, Woolf CJ (2004) Peripheral noxious stimulation induces phosphorylation of the NMDA receptor NR1 subunit at the PKC-dependent site, serine-896, in spinal cord dorsal horn neurons. Eur J NeuroSci 20:375–384PubMedGoogle Scholar
  245. 245.
    Caudle RM, Perez FM, Del Valle-Pinero AY, Iadarola MJ (2005) Spinal cord NR1 serine phosphorylation and NR2B subunit suppression following peripheral inflammation. Mol Pain 1:25PubMedGoogle Scholar
  246. 246.
    Gaunitz C, Schuttler A, Gillen C, Allgaier C (2002) Formalin-induced changes of NMDA receptor subunit expression in the spinal cord of the rat. Amino Acids 23:177–182PubMedGoogle Scholar
  247. 247.
    Pellegrini-Giampietro DE, Fan S, Ault B, Miller BE, Zukin RS (1994) Glutamate receptor gene expression in spinal cord of arthritic rats. J Neurosci 14:1576–1583PubMedGoogle Scholar
  248. 248.
    Ultenius C, Linderoth B, Meyerson BA, Wallin J (2006) Spinal NMDA receptor phosphorylation correlates with the presence of neuropathic signs following peripheral nerve injury in the rat. Neurosci Lett 399:85–90PubMedGoogle Scholar
  249. 249.
    Yang X, Yang H-B, Xie Q-J, Liu X-H, Hu X-D (2009) Peripheral inflammation increased the synaptic expression of NMDA receptors in spinal dorsal horn. Pain 144:162–169PubMedGoogle Scholar
  250. 250.
    Zou X, Lin Q, Willis WD (2000) Enhanced phosphorylation of NMDA receptor 1 subunits in spinal cord dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. J Neurosci 20:6989–6997PubMedGoogle Scholar
  251. 251.
    Wang S, Lim G, Zeng Q, Sung B, Yang L, Mao J (2005) Central glucocorticoid receptors modulate the expression and function of spinal NMDA receptors after peripheral nerve injury. J Neurosci 25:488–495PubMedGoogle Scholar
  252. 252.
    Hama AT, Unnerstall JR, Siegan JB, Sagen J (1995) Modulation of NMDA receptor expression in the rat spinal cord by peripheral nerve injury and adrenal medullary grafting. Brain Res 687:103–113PubMedGoogle Scholar
  253. 253.
    Wilson JA, Garry EM, Anderson HA, Rosie R, Colvin LA, Mitchell R, Fleetwood-Walker SM (2005) NMDA receptor antagonist treatment at the time of nerve injury prevents injury-induced changes in spinal NR1 and NR2B subunit expression and increases the sensitivity of residual pain behaviours to subsequently administered NMDA receptor antagonists. Pain 117:421–432PubMedGoogle Scholar
  254. 254.
    Lee J, Ro JY (2007) Differential regulation of glutamate receptors in trigeminal ganglia following masseter inflammation. Neurosci Lett 421:91–95PubMedGoogle Scholar
  255. 255.
    Wang H, Zhang RX, Wang R, Qiao JT (1999) Decreased expression of N-methyl-d-aspartate (NMDA) receptors in rat dorsal root ganglion following complete Freund’s adjuvant-induced inflammation: an immunocytochemical study for NMDA NR1 subunit. Neurosci Lett 265:195–198PubMedGoogle Scholar
  256. 256.
    Carlton SM, Coggeshall RE (1999) Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res 820:63–70PubMedGoogle Scholar
  257. 257.
    Du J, Zhou S, Coggeshall RE, Carlton SM (2003) N-methyl-d-aspartate-induced excitation and sensitization of normal and inflamed nociceptors. Neuroscience 118:547–562PubMedGoogle Scholar
  258. 258.
    Dougherty PM, Willis WD (1992) Enhanced responses of spinothalamic tract neurons to excitatory amino acids accompany capsaicin-induced sensitization in the monkey. J Neurosci 12:883–894PubMedGoogle Scholar
  259. 259.
    Isaev D, Gerber G, Park SK, Chung JM, Randić M (2000) Facilitation of NMDA-induced currents and Ca2+ transients in the rat substantia gelatinosa neurons after ligation of L5–L6 spinal nerves. NeuroReport 11:4055–4061PubMedGoogle Scholar
  260. 260.
    Guo H, Huang LY (2001) Alteration in the voltage dependence of NMDA receptor channels in rat dorsal horn neurones following peripheral inflammation. J Physiol 537:115–123PubMedGoogle Scholar
  261. 261.
    Zou X, Lin Q, Willis WD (2002) Role of protein kinase A in phosphorylation of NMDA receptor 1 subunits in dorsal horn and spinothalamic tract neurons after intradermal injection of capsaicin in rats. Neuroscience 115:775–786PubMedGoogle Scholar
  262. 262.
    Gao X, Kim HK, Chung JM, Chung K (2005) Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats. Pain 116:62–72PubMedGoogle Scholar
  263. 263.
    Zhang X, Wu J, Lei Y, Fang L, Willis WD (2005) Protein phosphatase modulates the phosphorylation of spinal cord NMDA receptors in rats following intradermal injection of capsaicin. Brain Res Mol Brain Res 138:264–272PubMedGoogle Scholar
  264. 264.
    Chen BS, Roche KW (2007) Regulation of NMDA receptors by phosphorylation. Neuropharmacology 53:362–368PubMedGoogle Scholar
  265. 265.
    Guo W, Zou S, Guan Y, Ikeda T, Tal M, Dubner R, Ren K (2002) Tyrosine phosphorylation of the NR2B subunit of the NMDA receptor in the spinal cord during the development and maintenance of inflammatory hyperalgesia. J Neurosci 22:6208–6217PubMedGoogle Scholar
  266. 266.
    Guo W, Wei F, Zou S, Robbins MT, Sugiyo S, Ikeda T, Tu JC, Worley PF, Dubner R, Ren K (2004) Group I metabotropic glutamate receptor NMDA receptor coupling and signaling cascade mediate spinal dorsal horn NMDA receptor 2B tyrosine phosphorylation associated with inflammatory hyperalgesia. J Neurosci 24:9161–9173PubMedGoogle Scholar
  267. 267.
    Slack S, Battaglia A, Cibert-Goton V, Gavazzi I (2008) EphrinB2 induces tyrosine phosphorylation of NR2B via Src-family kinases during inflammatory hyperalgesia. Neuroscience 156:175–183PubMedGoogle Scholar
  268. 268.
    Pezet S, Marchand F, D’Mello R, Grist J, Clark AK, Malcangio M, Dickenson AH, Williams RJ, McMahon SB (2008) Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions. J Neurosci 28:4261–4270PubMedGoogle Scholar
  269. 269.
    Salter MW, Kalia LV (2004) Src kinases: a hub for NMDA receptor regulation. Nat Rev Neurosci 5:317–328PubMedGoogle Scholar
  270. 270.
    Zahn PK, Umali E, Brennan TJ (1998) Intrathecal non-NMDA excitatory amino acid receptor antagonists inhibit pain behaviors in a rat model of postoperative pain. Pain 74:213–223PubMedGoogle Scholar
  271. 271.
    Pogatzki EM, Niemeier JS, Sorkin LS, Brennan TJ (2003) Spinal glutamate receptor antagonists differentiate primary and secondary mechanical hyperalgesia caused by incision. Pain 105:97–107PubMedGoogle Scholar
  272. 272.
    Neugebauer V, Lucke T, Schaible HG (1993) N-methyl-d-aspartate (NMDA) and non-NMDA receptor antagonists block the hyperexcitability of dorsal horn neurons during development of acute arthritis in rat’s knee joint. J Neurophysiol 70:1365–1377PubMedGoogle Scholar
  273. 273.
    Spraggins DS, Turnbach ME, Randich A (2001) Effects of glutamate receptor antagonists on spinal dorsal horn neurons during zymosan-induced inflammation in rats. J Pain 2:12–24PubMedGoogle Scholar
  274. 274.
    Leem JW, Choi EJ, Park ES, Paik KS (1996) N-methyl-d-aspartate (NMDA) and non-NMDA glutamate receptor antagonists differentially suppress dorsal horn neuron responses to mechanical stimuli in rats with peripheral nerve injury. Neurosci Lett 211:37–40PubMedGoogle Scholar
  275. 275.
    Chaplan SR, Malmberg AB, Yaksh TL (1997) Efficacy of spinal NMDA receptor antagonism in formalin hyperalgesia and nerve injury evoked allodynia in the rat. J Pharmacol Exp Ther 280:829–838PubMedGoogle Scholar
  276. 276.
    Fang L, Wu J, Zhang X, Lin Q, Willis WD (2003) Increased phosphorylation of the GluR1 subunit of spinal cord α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor in rats following intradermal injection of capsaicin. Neuroscience 122:237–245PubMedGoogle Scholar
  277. 277.
    Lu Y, Sun YN, Wu X, Sun Q, Liu FY, Xing GG, Wan Y (2008) Role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor subunit GluR1 in spinal dorsal horn in inflammatory nociception and neuropathic nociception in rat. Brain Res 1200:19–26PubMedGoogle Scholar
  278. 278.
    Park JS, Voitenko N, Petralia RS, Guan X, Xu JT, Steinberg JP, Takamiya K, Sotnik A, Kopach O, Huganir RL, Tao YX (2009) Persistent inflammation induces GluR2 internalization via NMDA receptor-triggered PKC activation in dorsal horn neurons. J Neurosci 29:3206–3219PubMedGoogle Scholar
  279. 279.
    Park J-S, Yaster M, Guan X, Xu J-T, Shih M-H, Guan Y, Raja S, Tao Y-X (2008) Role of spinal cord α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in complete Freund’s adjuvant-induced inflammatory pain. Mol Pain 4:67PubMedGoogle Scholar
  280. 280.
    Zhou QQ, Imbe H, Zou S, Dubner R, Ren K (2001) Selective upregulation of the flip-flop splice variants of AMPA receptor subunits in the rat spinal cord after hindpaw inflammation. Brain Res Mol Brain Res 88:186–193PubMedGoogle Scholar
  281. 281.
    Florenzano F, De Luca B (1999) Nociceptive stimulation induces glutamate receptor down-regulation in the trigeminal nucleus. Neuroscience 90:201–207PubMedGoogle Scholar
  282. 282.
    Harris JA, Corsi M, Quartaroli M, Arban R, Bentivoglio M (1996) Upregulation of spinal glutamate receptors in chronic pain. Neuroscience 74:7–12PubMedGoogle Scholar
  283. 283.
    Lim J, Lim G, Sung B, Wang S, Mao J (2006) Intrathecal midazolam regulates spinal AMPA receptor expression and function after nerve injury in rats. Brain Res 1123:80–88PubMedGoogle Scholar
  284. 284.
    Garry EM, Moss A, Rosie R, Delaney A, Mitchell R, Fleetwood-Walker SM (2003) Specific involvement in neuropathic pain of AMPA receptors and adapter proteins for the GluR2 subunit. Mol Cell Neurosci 24:10–22PubMedGoogle Scholar
  285. 285.
    Yang L, Zhang FX, Huang F, Lu YJ, Li GD, Bao L, Xiao HS, Zhang X (2004) Peripheral nerve injury induces trans-synaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord. Eur J NeuroSci 19:871–883PubMedGoogle Scholar
  286. 286.
    Voitenko N, Gerber G, Youn D, Randić M (2004) Peripheral inflammation-induced increase of AMPA-mediated currents and Ca2+ transients in the presence of cyclothiazide in the rat substantia gelatinosa neurons. Cell Calcium 35:461–469PubMedGoogle Scholar
  287. 287.
    Oh MC, Derkach VA (2005) Dominant role of the GluR2 subunit in regulation of AMPA receptors by CaMKII. Nat Neurosci 8:853–854PubMedGoogle Scholar
  288. 288.
    Fang L, Wu J, Lin Q, Willis WD (2003) Protein kinases regulate the phosphorylation of the GluR1 subunit of AMPA receptors of spinal cord in rats following noxious stimulation. Brain Res Mol Brain Res 118:160–165PubMedGoogle Scholar
  289. 289.
    Katano T, Furue H, Okuda-Ashitaka E, Tagaya M, Watanabe M, Yoshimura M, Ito S (2008) N-ethylmaleimide-sensitive fusion protein (NSF) is involved in central sensitization in the spinal cord through GluR2 subunit composition switch after inflammation. Eur J NeuroSci 27:3161–3170PubMedGoogle Scholar
  290. 290.
    Elias GM, Nicoll RA (2007) Synaptic trafficking of glutamate receptors by MAGUK scaffolding proteins. Trends Cell Biol 17:343–352PubMedGoogle Scholar
  291. 291.
    Gardoni F, Marcello E, Di Luca M (2009) Postsynaptic density-membrane associated guanylate kinase proteins (PSD-MAGUKs) and their role in CNS disorders. Neuroscience 158:324–333PubMedGoogle Scholar
  292. 292.
    Tao F, Tao YX, Gonzalez JA, Fang M, Mao P, Johns RA (2001) Knockdown of PSD-95/SAP90 delays the development of neuropathic pain in rats. NeuroReport 12:3251–3255PubMedGoogle Scholar
  293. 293.
    Tao F, Tao YX, Mao P, Johns RA (2003) Role of postsynaptic density protein-95 in the maintenance of peripheral nerve injury-induced neuropathic pain in rats. Neuroscience 117:731–739PubMedGoogle Scholar
  294. 294.
    Migaud M, Charlesworth P, Dempster M, Webster LC, Watabe AM, Makhinson M, He Y, Ramsay MF, Morris RG, Morrison JH, O’Dell TJ, Grant SG (1998) Enhanced long-term potentiation and impaired learning in mice with mutant postsynaptic density-95 protein. Nature 396:433–439PubMedGoogle Scholar
  295. 295.
    Tao F, Su Q, Johns RA (2008) Cell-permeable peptide Tat-PSD-95 PDZ2 inhibits chronic inflammatory pain behaviors in mice. Mol Ther 16:1776–1782PubMedGoogle Scholar
  296. 296.
    Florio SK, Loh C, Huang SM, Iwamaye AE, Kitto KF, Fowler KW, Treiberg JA, Hayflick JS, Walker JM, Fairbanks CA, Lai Y (2009) Disruption of nNOS-PSD95 protein-protein interaction inhibits acute thermal hyperalgesia and chronic mechanical allodynia in rodents. Br J Pharmacol 158:494–506PubMedGoogle Scholar
  297. 297.
    Tao YX, Rumbaugh G, Wang GD, Petralia RS, Zhao C, Kauer FW, Tao F, Zhuo M, Wenthold RJ, Raja SN, Huganir RL, Bredt DS, Johns RA (2003) Impaired NMDA receptor-mediated postsynaptic function and blunted NMDA receptor-dependent persistent pain in mice lacking postsynaptic density-93 protein. J Neurosci 23:6703–6712PubMedGoogle Scholar
  298. 298.
    Zhang B, Tao F, Liaw WJ, Bredt DS, Johns RA, Tao YX (2003) Effect of knock down of spinal cord PSD-93/chapsin-110 on persistent pain induced by complete Freund’s adjuvant and peripheral nerve injury. Pain 106:187–196PubMedGoogle Scholar
  299. 299.
    Mauceri D, Cattabeni F, Di Luca M, Gardoni F (2004) Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines. J Biol Chem 279:23813–23821PubMedGoogle Scholar
  300. 300.
    Allen Spinal Cord Atlas [Internet]. Seattle (WA): Allen Institute for Brain Science. ©2009. Available from: http://mousespinal.brain-map.org.
  301. 301.
    Sans N, Petralia RS, Wang YX, Blahos J 2nd, Hell JW, Wenthold RJ (2000) A developmental change in NMDA receptor-associated proteins at hippocampal synapses. J Neurosci 20:1260–1271PubMedGoogle Scholar
  302. 302.
    Tao YX, Huang YZ, Mei L, Johns RA (2000) Expression of PSD-95/SAP90 is critical for N-methyl-d-aspartate receptor-mediated thermal hyperalgesia in the spinal cord. Neuroscience 98:201–206PubMedGoogle Scholar
  303. 303.
    Hanley JG (2008) PICK1: a multi-talented modulator of AMPA receptor trafficking. Pharmacol Ther 118:152–160PubMedGoogle Scholar
  304. 304.
    Li P, Kerchner GA, Sala C, Wei F, Huettner JE, Sheng M, Zhuo M (1999) AMPA receptor-PDZ interactions in facilitation of spinal sensory synapses. Nat Neurosci 2:972–977PubMedGoogle Scholar
  305. 305.
    Milstein AD, Nicoll RA (2008) Regulation of AMPA receptor gating and pharmacology by TARP auxiliary subunits. Trends Pharmacol Sci 29:333–339PubMedGoogle Scholar
  306. 306.
    Payne HL (2008) The role of transmembrane AMPA receptor regulatory proteins (TARPs) in neurotransmission and receptor trafficking (Review). Mol Membr Biol 25:353–362PubMedGoogle Scholar
  307. 307.
    Sager C, Tapken D, Kott S, Hollmann M (2009) Functional modulation of AMPA receptors by transmembrane AMPA receptor regulatory proteins. Neuroscience 158:45–54PubMedGoogle Scholar
  308. 308.
    Kato AS, Siuda ER, Nisenbaum ES, Bredt DS (2008) AMPA receptor subunit-specific regulation by a distinct family of type II TARPs. Neuron 59:986–996PubMedGoogle Scholar
  309. 309.
    Ziff EB (2007) TARPs and the AMPA receptor trafficking paradox. Neuron 53:627–633PubMedGoogle Scholar
  310. 310.
    Tao F, Skinner J, Su Q, Johns RA (2006) New role for spinal Stargazin in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-mediated pain sensitization after inflammation. J Neurosci Res 84:867–873PubMedGoogle Scholar
  311. 311.
    Schwenk J, Harmel N, Zolles G, Bildl W, Kulik A, Heimrich B, Chisaka O, Jonas P, Schulte U, Fakler B, Klocker N (2009) Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323:1313–1319PubMedGoogle Scholar
  312. 312.
    Zhang W, St-Gelais F, Grabner CP, Trinidad JC, Sumioka A, Morimoto-Tomita M, Kim KS, Straub C, Burlingame AL, Howe JR, Tomita S (2009) A transmembrane accessory subunit that modulates kainate-type glutamate receptors. Neuron 61:385–396PubMedGoogle Scholar
  313. 313.
    Ng D, Pitcher GM, Szilard RK, Sertie A, Kanisek M, Clapcote SJ, Lipina T, Kalia LV, Joo D, McKerlie C, Cortez M, Roder JC, Salter MW, McInnes RR (2009) Neto1 is a novel CUB-domain NMDA receptor-interacting protein required for synaptic plasticity and learning. PLoS Biol 7:e41PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2009

Authors and Affiliations

  1. 1.Department of Anatomy and Centre for Molecular Biology and NeuroscienceUniversity of OsloOsloNorway

Personalised recommendations