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. 2012 Feb 29;28(2):111–120. doi: 10.1007/s12264-012-1204-z

AMPA receptor trafficking in inflammation-induced dorsal horn central sensitization

Yuan-Xiang Tao 1,✉
PMCID: PMC3324122  NIHMSID: NIHMS355007  PMID: 22466122

Abstract

Activity-dependent postsynaptic receptor trafficking is critical for long-term synaptic plasticity in the brain, but it is unclear whether this mechanism actually mediates the spinal cord dorsal horn central sensitization (a specific form of synaptic plasticity) that is associated with persistent pain. Recent studies have shown that peripheral inflammation drives changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit trafficking in the dorsal horn and that such changes contribute to the hypersensitivity that underlies persistent pain. Here, we review current evidence to illustrate how spinal cord AMPARs participate in the dorsal horn central sensitization associated with persistent pain. Understanding these mechanisms may allow the development of novel therapeutic strategies for treating persistent pain.

Keywords: dorsal horn, GluA1, GluA2, inflammation, persistent pain, receptor trafficking

References

  • [1].Scholz J., Woolf C.J. Can we conquer pain? Nat Neurosci. 2002;5(Suppl):1062–1067. doi: 10.1038/nn942. [DOI] [PubMed] [Google Scholar]
  • [2].Burnashev N., Monyer H., Seeburg P.H., Sakmann B. Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron. 1992;8(1):189–198. doi: 10.1016/0896-6273(92)90120-3. [DOI] [PubMed] [Google Scholar]
  • [3].Hollmann M., Heinemann S. Cloned glutamate receptors. Annu Rev Neurosci. 1994;17:31–108. doi: 10.1146/annurev.ne.17.030194.000335. [DOI] [PubMed] [Google Scholar]
  • [4].Tao Y.X. Dorsal horn alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking in inflammatory pain. Anesthesiology. 2010;112(5):1259–1265. doi: 10.1097/ALN.0b013e3181d3e1ed. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [5].Mao J., Price D.D., Hayes R.L., Lu J., Mayer D.J. Differential roles of NMDA and non-NMDA receptor activation in induction and maintenance of thermal hyperalgesia in rats with painful peripheral mononeuropathy. Brain Res. 1992;598(1–2):271–278. doi: 10.1016/0006-8993(92)90193-D. [DOI] [PubMed] [Google Scholar]
  • [6].Garry E.M., Moss A., Rosie R., Delaney A., Mitchell R., Fleetwood-Walker S.M. Specific involvement in neuropathic pain of AMPA receptors and adapter proteins for the GluR2 subunit. Mol Cell Neurosci. 2003;24(1):10–22. doi: 10.1016/S1044-7431(03)00134-9. [DOI] [PubMed] [Google Scholar]
  • [7].Sorkin L.S., Yaksh T.L., Doom C.M. Mechanical allodynia in rats is blocked by a Ca2+ permeable AMPA receptor antagonist. Neuroreport. 1999;10(17):3523–3526. doi: 10.1097/00001756-199911260-00011. [DOI] [PubMed] [Google Scholar]
  • [8].Sorkin L.S., Yaksh T.L., Doom C.M. Pain models display differential sensitivity to Ca2+-permeable non-NMDA glutamate receptor antagonists. Anesthesiology. 2001;95(4):965–973. doi: 10.1097/00000542-200110000-00028. [DOI] [PubMed] [Google Scholar]
  • [9].Park J.S., Yaster M., Guan X., Xu J.T., Shih M.H., Guan Y., et al. Role of spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors in complete Freund’s adjuvant-induced inflammatory pain. Mol Pain. 2008;4(1):67. doi: 10.1186/1744-8069-4-67. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [10].Seagrove L.C., Suzuki R., Dickenson A.H. Electrophysiological characterisations of rat lamina I dorsal horn neurones and the involvement of excitatory amino acid receptors. Pain. 2004;108(1–2):76–87. doi: 10.1016/j.pain.2003.12.004. [DOI] [PubMed] [Google Scholar]
  • [11].Stanfa L.C., Hampton D.W., Dickenson A.H. Role of Ca2+-permeable non-NMDA glutamate receptors in spinal nociceptive transmission. Neuroreport. 2000;11(14):3199–3202. doi: 10.1097/00001756-200009280-00030. [DOI] [PubMed] [Google Scholar]
  • [12].Hartmann B., Ahmadi S., Heppenstall P.A., Lewin G.R., Schott C., Borchardt T., et al. The AMPA receptor subunits GluR-A and GluRB reciprocally modulate spinal synaptic plasticity and inflammatory pain. Neuron. 2004;44(4):637–650. doi: 10.1016/j.neuron.2004.10.029. [DOI] [PubMed] [Google Scholar]
  • [13].Collingridge G.L., Isaac J.T., Wang Y.T. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci. 2004;5(12):952–962. doi: 10.1038/nrn1556. [DOI] [PubMed] [Google Scholar]
  • [14].Song I., Huganir R.L. Regulation of AMPA receptors during synaptic plasticity. Trends Neurosci. 2002;25(11):578–588. doi: 10.1016/S0166-2236(02)02270-1. [DOI] [PubMed] [Google Scholar]
  • [15].Engelman H.S., Allen T.B., MacDermott A.B. The distribution of neurons expressing calcium-permeable AMPA receptors in the superficial laminae of the spinal cord dorsal horn. J Neurosci. 1999;19(6):2081–2089. doi: 10.1523/JNEUROSCI.19-06-02081.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Fletcher E.J., Lodge D. New developments in the molecular pharmacology of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate and kainate receptors. Pharmacol Ther. 1996;70(1):65–89. doi: 10.1016/0163-7258(96)00014-9. [DOI] [PubMed] [Google Scholar]
  • [17].Furuyama T., Kiyama H., Sato K., Park H.T., Maeno H., Takagi H., et al. 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. 1993;18(1–2):141–151. doi: 10.1016/0169-328X(93)90183-P. [DOI] [PubMed] [Google Scholar]
  • [18].Polgar E., Al Ghamdi K.S., Todd A.J. Two populations of neurokinin 1 receptor-expressing projection neurons in lamina I of the rat spinal cord that differ in AMPA receptor subunit composition and density of excitatory synaptic input. Neuroscience. 2010;167(4):1192–1204. doi: 10.1016/j.neuroscience.2010.03.028. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [19].Galan A., Laird J.M., Cervero F. In vivo recruitment by painful stimuli of AMPA receptor subunits to the plasma membrane of spinal cord neurons. Pain. 2004;112(3):315–323. doi: 10.1016/j.pain.2004.09.011. [DOI] [PubMed] [Google Scholar]
  • [20].Larsson M., Broman J. Translocation of GluR1-containing AMPA receptors to a spinal nociceptive synapse during acute noxious stimulation. J Neurosci. 2008;28(28):7084–7090. doi: 10.1523/JNEUROSCI.5749-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [21].Choi J.I., Svensson C.I., Koehrn F.J., Bhuskute A., Sorkin L.S. Peripheral inflammation induces tumor necrosis factor dependent AMPA receptor trafficking and Akt phosphorylation in spinal cord in addition to pain behavior. Pain. 2010;149(2):243–253. doi: 10.1016/j.pain.2010.02.008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Pezet S., Marchand F., D’Mello R., Grist J., Clark A.K., Malcangio M., et al. Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions. J Neurosci. 2008;28(16):4261–4270. doi: 10.1523/JNEUROSCI.5392-07.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [23].Park J.S., Voitenko N., Petralia R.S., Guan X., Xu J.T., Steinberg J.P., et al. Persistent inflammation induces GluR2 internalization via NMDA receptor-triggered PKC activation in dorsal horn neurons. J Neurosci. 2009;29(10):3206–3219. doi: 10.1523/JNEUROSCI.4514-08.2009. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Katano T., Furue H., Okuda-Ashitaka E., Tagaya M., Watanabe M., Yoshimura M., et al. 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. 2008;27(12):3161–3170. doi: 10.1111/j.1460-9568.2008.06293.x. [DOI] [PubMed] [Google Scholar]
  • [25].Kopach O., Kao S.C., Petralia R.S., Belan P., Tao Y.X., Voitenko N. Inflammation alters trafficking of extrasynaptic AMPA receptors in tonically firing lamina II neurons of the rat spinal dorsal horn. Pain. 2011;152(4):912–923. doi: 10.1016/j.pain.2011.01.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Atianjoh F.E., Yaster M., Zhao X., Takamiya K., Xia J., Gauda E.B., et al. Spinal cord protein interacting with C kinase 1 is required for the maintenance of complete Freund’s adjuvant-induced inflammatory pain but not for incision-induced post-operative pain. Pain. 2010;151(1):226–234. doi: 10.1016/j.pain.2010.07.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [27].Wang W., Petralia R.S., Takamiya K., Xia J., Li Y.Q., Huganir R.L., et al. Preserved acute pain and impaired neuropathic pain in mice lacking protein interacting with C Kinase 1. Mol Pain. 2011;7:11. doi: 10.1186/1744-8069-7-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [28].Vikman K.S., Rycroft B.K., Christie M.J. 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. 2008;586(2):515–527. doi: 10.1113/jphysiol.2007.145581. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [29].Banke T.G., Bowie D., Lee H., Huganir R.L., Schousboe A., Traynelis S.F. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J Neurosci. 2000;20(1):89–102. doi: 10.1523/JNEUROSCI.20-01-00089.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Man H.Y., Sekine-Aizawa Y., Huganir R.L. Regulation of {alpha}-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking through PKA phosphorylation of the Glu receptor 1 subunit. Proc Natl Acad Sci U S A. 2007;104(9):3579–3584. doi: 10.1073/pnas.0611698104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [31].Oh M.C., Derkach V.A., Guire E.S., Soderling T.R. Extrasynaptic membrane trafficking regulated by GluR1 serine 845 phosphorylation primes AMPA receptors for long-term potentiation. J Biol Chem. 2006;281(2):752–758. doi: 10.1074/jbc.M509677200. [DOI] [PubMed] [Google Scholar]
  • [32].Derkach V., Barria A., Soderling T.R. Ca2+/calmodulin-kinase II enhances channel conductance of alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionate type glutamate receptors. Proc Natl Acad Sci U S A. 1999;96(6):3269–3274. doi: 10.1073/pnas.96.6.3269. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Hayashi Y., Shi S.H., Esteban J.A., Piccini A., Poncer J.C., Malinow R. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science. 2000;287(5461):2262–2267. doi: 10.1126/science.287.5461.2262. [DOI] [PubMed] [Google Scholar]
  • [34].Boehm J., Kang M.G., Johnson R.C., Esteban J., Huganir R.L., Malinow R. Synaptic incorporation of AMPA receptors during LTP is controlled by a PKC phosphorylation site on GluR1. Neuron. 2006;51(2):213–225. doi: 10.1016/j.neuron.2006.06.013. [DOI] [PubMed] [Google Scholar]
  • [35].Shen L., Liang F., Walensky L.D., Huganir R.L. Regulation of AMPA receptor GluR1 subunit surface expression by a 4. 1N-linked actin cytoskeletal association. J Neurosci. 2000;20(21):7932–7940. doi: 10.1523/JNEUROSCI.20-21-07932.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Lin D.T., Makino Y., Sharma K., Hayashi T., Neve R., Takamiya K., et al. Regulation of AMPA receptor extrasynaptic insertion by 4.1N, phosphorylation and palmitoylation. Nat Neurosci. 2009;12(7):879–887. doi: 10.1038/nn.2351. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [37].Fang L., Wu J., Zhang X., Lin Q., Willis W.D. Increased phosphorylation of the GluR1 subunit of spinal cord alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor in rats following intradermal injection of capsaicin. Neuroscience. 2003;122(1):237–245. doi: 10.1016/S0306-4522(03)00526-8. [DOI] [PubMed] [Google Scholar]
  • [38].Fang L., Wu J., Lin Q., Willis W.D. 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. 2003;118(1–2):160–165. doi: 10.1016/j.molbrainres.2003.08.002. [DOI] [PubMed] [Google Scholar]
  • [39].Lu Y., Sun Y.N., Wu X., Sun Q., Liu F.Y., Xing G.G., et al. Role of alpha-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. 2008;1200:19–26. doi: 10.1016/j.brainres.2008.01.012. [DOI] [PubMed] [Google Scholar]
  • [40].Dong H., O’Brien R.J., Fung E.T., Lanahan A.A., Worley P.F., Huganir R.L. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature. 1997;386(6622):279–284. doi: 10.1038/386279a0. [DOI] [PubMed] [Google Scholar]
  • [41].Dong H., Zhang P., Song I., Petralia R.S., Liao D., Huganir R.L. Characterization of the glutamate receptor-interacting proteins GRIP1 and GRIP2. J Neurosci. 1999;19(16):6930–6941. doi: 10.1523/JNEUROSCI.19-16-06930.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [42].Dong H., Zhang P., Liao D., Huganir R.L. Characterization, expression, and distribution of GRIP protein. Ann N Y Acad Sci. 1999;868:535–540. doi: 10.1111/j.1749-6632.1999.tb11323.x. [DOI] [PubMed] [Google Scholar]
  • [43].Dev K.K., Nakanishi S., Henley J.M. The PDZ domain of PICK1 differentially accepts protein kinase C-alpha and GluR2 as interacting ligands. J Biol Chem. 2004;279(40):41393–41397. doi: 10.1074/jbc.M404499200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [44].Perez J.L., Khatri L., Chang C., Srivastava S., Osten P., Ziff E.B. PICK1 targets activated protein kinase Calpha to AMPA receptor clusters in spines of hippocampal neurons and reduces surface levels of the AMPA-type glutamate receptor subunit 2. J Neurosci. 2001;21(15):5417–5428. doi: 10.1523/JNEUROSCI.21-15-05417.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [45].Staudinger J., Lu J., Olson E.N. Specific interaction of the PDZ domain protein PICK1 with the COOH terminus of protein kinase C-alpha. J Biol Chem. 1997;272(51):32019–32024. doi: 10.1074/jbc.272.51.32019. [DOI] [PubMed] [Google Scholar]
  • [46].Chung H.J., Xia J., Scannevin R.H., Zhang X., Huganir R.L. Phosphorylation of the AMPA receptor subunit GluR2 differentially regulates its interaction with PDZ domain-containing proteins. J Neurosci. 2000;20(19):7258–7267. doi: 10.1523/JNEUROSCI.20-19-07258.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [47].Matsuda S., Mikawa S., Hirai H. Phosphorylation of serine-880 in GluR2 by protein kinase C prevents its C terminus from binding with glutamate receptor-interacting protein. J Neurochem. 1999;73(4):1765–1768. doi: 10.1046/j.1471-4159.1999.731765.x. [DOI] [PubMed] [Google Scholar]
  • [48].Iwakura Y., Nagano T., Kawamura M., Horikawa H., Ibaraki K., Takei N., et al. N-methyl-D-aspartate-induced alpha-amino-3-hydroxy- 5-methyl-4-isoxazoleproprionic acid (AMPA) receptor downregulation involves interaction of the carboxyl terminus of GluR2/3 with Pick1. Ligand-binding studies using Sindbis vectors carrying AMPA receptor decoys. J Biol Chem. 2001;276(43):40025–40032. doi: 10.1074/jbc.M103125200. [DOI] [PubMed] [Google Scholar]
  • [49].Tigaret C.M., Thalhammer A., Rast G.F., Specht C.G., Auberson Y.P., Stewart M.G., et al. Subunit dependencies of N-methyl-D-aspartate (NMDA) receptor-induced alpha-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid (AMPA) receptor internalization. Mol Pharmacol. 2006;69(4):1251–1259. doi: 10.1124/mol.105.018580. [DOI] [PubMed] [Google Scholar]
  • [50].Moult P.R., Cross A., Santos S.D., Carvalho A.L., Lindsay Y., Connolly C.N., et al. Leptin regulates AMPA receptor trafficking via PTEN inhibition. J Neurosci. 2010;30(11):4088–4101. doi: 10.1523/JNEUROSCI.3614-09.2010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [51].Corera A.T., Doucet G., Fon E.A. Long-term potentiation in isolated dendritic spines. PLoS One. 2009;4(6):e6021. doi: 10.1371/journal.pone.0006021. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [52].Serulle Y., Zhang S., Ninan I., Puzzo D., McCarthy M., Khatri L., et al. A GluR1-cGKII interaction regulates AMPA receptor trafficking. Neuron. 2007;56(4):670–688. doi: 10.1016/j.neuron.2007.09.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [53].Kim M.J., Dunah A.W., Wang Y.T., Sheng M. Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron. 2005;46(5):745–760. doi: 10.1016/j.neuron.2005.04.031. [DOI] [PubMed] [Google Scholar]
  • [54].Braithwaite S.P., Xia H., Malenka R.C. Differential roles for NSF and GRIP/ABP in AMPA receptor cycling. Proc Natl Acad Sci U S A. 2002;99(10):7096–7101. doi: 10.1073/pnas.102156099. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [55].Hanley J.G., Khatri L., Hanson P.I., Ziff E.B. NSF ATPase and alpha-/beta-SNAPs disassemble the AMPA receptor-PICK1 complex. Neuron. 2002;34(1):53–67. doi: 10.1016/S0896-6273(02)00638-4. [DOI] [PubMed] [Google Scholar]
  • [56].Huang Y., Man H.Y., Sekine-Aizawa Y., Han Y., Juluri K., Luo H., et al. S-nitrosylation of N-ethylmaleimide sensitive factor mediates surface expression of AMPA receptors. Neuron. 2005;46(4):533–540. doi: 10.1016/j.neuron.2005.03.028. [DOI] [PubMed] [Google Scholar]
  • [57].Ji R.R., Kohno T., Moore K.A., Woolf C.J. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26(12):696–705. doi: 10.1016/j.tins.2003.09.017. [DOI] [PubMed] [Google Scholar]
  • [58].Latremoliere A., Woolf C.J. Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain. 2009;10(9):895–926. doi: 10.1016/j.jpain.2009.06.012. [DOI] [PMC free article] [PubMed] [Google Scholar]

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