Skip to main content
Neurotherapeutics logoLink to Neurotherapeutics
. 2009 Oct;6(4):693–702. doi: 10.1016/j.nurt.2009.07.008

Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain

Long-Jun Wu 1, Min Zhuo 1,2,
PMCID: PMC5084290  PMID: 19789073

Summary

Neuropathic pain is generally defined as a chronic pain state resulting from peripheral or central nerve injury, or both. An effective treatment for neuropathic pain is still lacking. The NMDA receptor, one type of the ionotropic glutamate receptors, is known to be important for triggering long-lasting changes in synapses. NMDA receptor-dependent synaptic plasticity plays roles not only in physiological functions such as learning and memory, but also in unwanted pathological conditions such as chronic pain. This review addresses recent progress on NMDA receptors in neuropathic pain, with particular emphasis on the NR2B-subunit-containing receptors. The expression and function of NMDA receptors in synaptic plasticity in the pain transmission pathway from dorsal root ganglia to the anterior cingulate cortex is reviewed, and preclinical and clinical investigations of selective NMDA receptor in neuropathic pain are discussed. The NMDA receptors, in particular NR2B-containing NMDA receptors, serve as promising targets for treatment of neuropathic pain.

Key Words: Neuropathic pain, glutamate, NR2B subunit, NMDA receptor, anterior cingulated cortex, Ro25-6981

References

  • 1.Wu M, Pang Z, Zhuo M, Xu Z. Prolonged membrane potential depolarization in cingulate pyramidal cells after digit amputation in adult rats. Mol Pain. 2005;1:23–23. doi: 10.1186/1744-8069-1-23. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Zhuo M. Neuronal mechanism for neuropathic pain. Mol Pain. 2007;3:14–14. doi: 10.1186/1744-8069-3-14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Zhuo M. Glutamate receptors and persistent pain: targeting forebrain NR2B subunits. Drug Discov Today. 2002;7:259–267. doi: 10.1016/S1359-6446(01)02138-9. [DOI] [PubMed] [Google Scholar]
  • 4.Chizh BA, Headley PM, Tzschentke TM. NMDA receptor antagonists as analgesics: focus on the NR2B subtype. Trends Pharmacol Sci. 2001;22:636–642. doi: 10.1016/S0165-6147(00)01863-0. [DOI] [PubMed] [Google Scholar]
  • 5.Childers WE, Baudy RB. N-methyl-d-aspartate antagonists and neuropathic pain: the search for relief. J Med Chem. 2007;50:2557–2562. doi: 10.1021/jm060728b. [DOI] [PubMed] [Google Scholar]
  • 6.Petrenko AB, Yamakura T, Baba H, Shimoji K. The role of N-methyl-d-aspartate (NMDA) receptors in pain: a review. Anesth Analg. 2003;97:1108–1116. doi: 10.1213/01.ANE.0000081061.12235.55. [DOI] [PubMed] [Google Scholar]
  • 7.Collingridge GL, Bliss TV. Memories of NMDA receptors and LTP. Trends Neurosci. 1995;18:54–56. doi: 10.1016/0166-2236(95)93868-X. [DOI] [PubMed] [Google Scholar]
  • 8.Cull-Candy S, Brickley S, Farrant M. NMDA receptor subunits: diversity, development and disease. Curr Opin Neurobiol. 2001;11:327–335. doi: 10.1016/S0959-4388(00)00215-4. [DOI] [PubMed] [Google Scholar]
  • 9.Chatterton JE, Awobuluyi M, Premkumar LS, et al. Excitatory glycine receptors containing the NR3 family of NMDA receptor subunits. Nature. 2002;415:793–798. doi: 10.1038/nature715. [DOI] [PubMed] [Google Scholar]
  • 10.Malenka RC, Bear MF. LTP and LTD: an embarrassment of riches. Neuron. 2004;44:5–21. doi: 10.1016/j.neuron.2004.09.012. [DOI] [PubMed] [Google Scholar]
  • 11.Benke D, Wenzel A, Scheuer L, Fritschy JM, Mohler H. Immunobiochemical characterization of the NMDA-receptor subunit NR1 in the developing and adult rat brain. J Recept Signal Transduct Res. 1995;15:393–411. doi: 10.3109/10799899509045229. [DOI] [PubMed] [Google Scholar]
  • 12.Laurie DJ, Bartke I, Schoepfer R, Naujoks K, Seeburg PH. Regional, developmental and interspecies expression of the four NMDAR2 subunits, examined using monoclonal antibodies. Brain Res Mol Brain Res. 1997;51:23–32. doi: 10.1016/S0169-328X(97)00206-4. [DOI] [PubMed] [Google Scholar]
  • 13.Liu H, Mantyh PW, Basbaum AI. NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature. 1997;386:721–724. doi: 10.1038/386721a0. [DOI] [PubMed] [Google Scholar]
  • 14.Marvizón JC, McRoberts JA, Ennes HS, et al. Two N-methyl-d-aspartate receptors in rat dorsal root ganglia with different subunit composition and localization. J Comp Neurol. 2002;446:325–341. doi: 10.1002/cne.10202. [DOI] [PubMed] [Google Scholar]
  • 15.Karlsson U, Sjödin J, Angeby Möller K, Johansson S, Wikström L, Näsström J. Glutamate-induced currents reveal three functionally distinct NMDA receptor populations in rat dorsal horn: effects of peripheral nerve lesion and inflammation. Neuroscience. 2002;112:861–868. doi: 10.1016/S0306-4522(02)00140-9. [DOI] [PubMed] [Google Scholar]
  • 16.Watanabe M, Inoue Y, Sakimura K, Mishina M. Developmental changes in distribution of NMDA receptor channel subunit mRNAs. Neuroreport. 1992;3:1138–1140. doi: 10.1097/00001756-199212000-00027. [DOI] [PubMed] [Google Scholar]
  • 17.Boyce S, Wyatt A, Webb JK, et al. Selective NMDA NR2B antagonists induce antinociception without motor dysfunction: correlation with restricted localisation of NR2B subunit in dorsal horn. Neuropharmacology. 1999;38:611–623. doi: 10.1016/S0028-3908(98)00218-4. [DOI] [PubMed] [Google Scholar]
  • 18.Miki K, Zhou QQ, Guo W, et al. Changes in gene expression and neuronal phenotype in brain stem pain modulatory circuitry after inflammation. J Neurophysiol. 2002;87:750–760. doi: 10.1152/jn.00534.2001. [DOI] [PubMed] [Google Scholar]
  • 19.Dracheva S, Byne W, Chin B, Haroutunian V. Ionotropic glutamate receptor mRNA expression in the human thalamus: absence of change in schizophrenia. Brain Res. 2008;1214:23–34. doi: 10.1016/j.brainres.2008.03.039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Monyer H, Burnashev N, Laurie DJ, Sakmann B, Seeburg PH. Developmental and regional expression in the rat brain and functional properties of four NMDA receptors. Neuron. 1994;12:529–540. doi: 10.1016/0896-6273(94)90210-0. [DOI] [PubMed] [Google Scholar]
  • 21.Zhuo M. Plasticity of NMDA receptor NR2B subunit in memory and chronic pain. Mol Brain. 2009;2:4–4. doi: 10.1186/1756-6606-2-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science. 2000;288:1765–1769. doi: 10.1126/science.288.5472.1765. [DOI] [PubMed] [Google Scholar]
  • 23.Ji RR, Kohno T, Moore KA, Woolf CJ. Central sensitization and LTP: do pain and memory share similar mechanisms? Trends Neurosci. 2003;26:696–705. doi: 10.1016/j.tins.2003.09.017. [DOI] [PubMed] [Google Scholar]
  • 24.Sandkühler J. Understanding LTP in pain pathways. Mol Pain. 2007;3:9–9. doi: 10.1186/1744-8069-3-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Wei F, Vadakkan Kl, Toyoda H, et al. Calcium calmodulin-stimulated adenylyl cyclases contribute to activation of extracellular signal-regulated kinase in spinal dorsal horn neurons in adult rats and mice. J Neurosci. 2006;26:851–861. doi: 10.1523/JNEUROSCI.3292-05.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Qu XX, Cai J, Li MJ, et al. Role of the spinal cord NR2B-containing NMDA receptors in the development of neuropathic pain. Exp Neurol. 2009;215:298–307. doi: 10.1016/j.expneurol.2008.10.018. [DOI] [PubMed] [Google Scholar]
  • 27.Pedersen LM, Gjerstad J. Spinal cord long-term potentiation is attenuated by the NMDA-2B receptor antagonist Ro 25-6981. Acta Physiol (Oxf) 2008;192:421–427. doi: 10.1111/j.1748-1716.2007.01756.x. [DOI] [PubMed] [Google Scholar]
  • 28.Zhang HM, Zhou LJ, Hu XD, Hu NW, Zhang T, Liu XG. Acute nerve injury induces long-term potentiation of C-fiber evoked field potentials in spinal dorsal horn of intact rat. Sheng Li Xue Bao. 2004;56:591–596. [PubMed] [Google Scholar]
  • 29.Ikeda H, Stark J, Fischer H, et al. Synaptic amplifier of inflammatory pain in the spinal dorsal horn. Science. 2006;312:1659–1662. doi: 10.1126/science.1127233. [DOI] [PubMed] [Google Scholar]
  • 30.Lenz FA, Gracely RH, Romanoski AJ, Hope EJ, Rowland LH, Dougherty PM. Stimulation in the human somatosensory thalamus can reproduce both the affective and sensory dimensions of previously experienced pain. Nat Med. 1995;1:910–913. doi: 10.1038/nm0995-910. [DOI] [PubMed] [Google Scholar]
  • 31.Banati RB, Cagnin A, Brooks DJ, et al. Long-term trans-synaptic glial responses in the human thalamus after peripheral nerve injury. Neuroreport. 2001;12:3439–3442. doi: 10.1097/00001756-200111160-00012. [DOI] [PubMed] [Google Scholar]
  • 32.Landisman CE, Connors BW. Long-term modulation of electrical synapses in the mammalian thalamus. Science. 2005;310:1809–1813. doi: 10.1126/science.1114655. [DOI] [PubMed] [Google Scholar]
  • 33.Carson LV, Kelahan AM, Ray RH, Massey CE, Doetsch GS. Effects of early peripheral lesions on the somatotopic organization of the cerebral cortex. Clin Neurosurg. 1981;28:532–546. doi: 10.1093/neurosurgery/28.cn_suppl_1.532. [DOI] [PubMed] [Google Scholar]
  • 34.Wei F, Qiu CS, Liauw J, et al. Calcium calmodulin-dependent protein kinase IV is required for fear memory. Nat Neurosci. 2002;5:573–579. doi: 10.1038/nn0602-855. [DOI] [PubMed] [Google Scholar]
  • 35.Isaac JT, Crair MC, Nicoll RA, Malenka RC. Silent synapses during development of fhalamocortical inputs. Neuron. 1997;18:269–280. doi: 10.1016/S0896-6273(00)80267-6. [DOI] [PubMed] [Google Scholar]
  • 36.Price DD. Psychological and neural mechanisms of the affective dimension of pain. Science. 2000;288:1769–1772. doi: 10.1126/science.288.5472.1769. [DOI] [PubMed] [Google Scholar]
  • 37.Wei F, Wang GD, Kerchner GA, et al. Genetic enhancement of inflammatory pain by forebrain NR2B overexpression. Nat Neurosci. 2001;4:164–169. doi: 10.1038/83993. [DOI] [PubMed] [Google Scholar]
  • 38.Escobar ML, Chao V, Bermúdez-Rattoni F. In vivo long-term potentiation in the insular cortex: NMDA receptor dependence. Brain Res. 1998;779:314–319. doi: 10.1016/S0006-8993(97)01175-X. [DOI] [PubMed] [Google Scholar]
  • 39.Casey KL. Forebrain mechanisms of nociception and pain: analysis through imaging. Proc Natl Acad Sci U S A. 1999;96:7668–7674. doi: 10.1073/pnas.96.14.7668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Calejesan AA, Kim SJ, Zhuo M. Descending facilitatory modulation of a behavioral nociceptive response by stimulation in the adult rat anterior cingulate cortex. Eur J Pain. 2000;4:83–96. doi: 10.1053/eujp.1999.0158. [DOI] [PubMed] [Google Scholar]
  • 41.Tang J, Ko S, Ding HK, Qiu CS, Calejesan AA, Zhuo M. Pavlovian fear memory induced by activation in the anterior cingulate cortex. Mol Pain. 2005;1:6–6. doi: 10.1186/1744-8069-1-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 42.Wei F, Qiu CS, Kim SJ, et al. Genetic elimination of behavioral sensitization in mice lacking calmodulin-stimulated adenylyl cyclases. Neuron. 2002;36:713–726. doi: 10.1016/S0896-6273(02)01019-X. [DOI] [PubMed] [Google Scholar]
  • 43.Wei F, Xia XM, Tang J, et al. Calmodulin regulates synaptic plasticity in the anterior cingulate cortex and behavioral responses: a microelectroporation study in adult rodents. J Neurosci. 2003;23:8402–8409. doi: 10.1523/JNEUROSCI.23-23-08402.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.Liauw J, Wu LJ, Zhuo M. Calcium-stimulated adenylyl cyclases required for long-term potentiation in the anterior cingulate cortex. J Neurophysiol. 2005;94:878–882. doi: 10.1152/jn.01205.2004. [DOI] [PubMed] [Google Scholar]
  • 45.Zhao MG, Toyoda H, Lee YS, et al. Roles of NMDA NR2B subtype receptor in prefrontal long-term potentiation and contextual fear memory. Neuron. 2005;47:859–872. doi: 10.1016/j.neuron.2005.08.014. [DOI] [PubMed] [Google Scholar]
  • 46.Wei F, Zhuo M. Potentiation of sensory responses in the anterior cingulate cortex following digit amputation in the anaesthetised rat. J Physiol. 2001;532:823–833. doi: 10.1111/j.1469-7793.2001.0823e.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Zhuo M. Central plasticity in pathological pain. Novartis Found Symp. 2004;261:132–145. doi: 10.1002/0470869127.ch10. [DOI] [PubMed] [Google Scholar]
  • 48.Paoletti P, Neyton J. NMDA receptor subunits: function and pharmacology. Curr Opin Pharmacol. 2007;7:39–47. doi: 10.1016/j.coph.2006.08.011. [DOI] [PubMed] [Google Scholar]
  • 49.Gogas KR. Glutamate-based therapeutic approaches: NR2B receptor antagonists. Curr Opin Pharmacol. 2006;6:68–74. doi: 10.1016/j.coph.2005.11.001. [DOI] [PubMed] [Google Scholar]
  • 50.Fischer G, Mutel V, Trube G, et al. Ro 25-6981, a highly potent and selective blocker of N-methyl-d-aspartate receptors containing the NR2B subunit: characterization in vitro. J Pharmacol Exp Ther. 1997;283:1285–1292. [PubMed] [Google Scholar]
  • 51.Williams K. Ifenprodil discriminates subtypes of the N-methyl-d-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol Pharmacol. 1993;44:851–859. [PubMed] [Google Scholar]
  • 52.Auberson YP, Allgeier H, Bischoff S, Lingenhoehl K, Moretti R, Schmutz M. 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition. Bioorg Med Chem Lett. 2002;12:1099–1102. doi: 10.1016/S0960-894X(02)00074-4. [DOI] [PubMed] [Google Scholar]
  • 53.Liu L, Wong TP, Pozza MF, et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science. 2004;304:1021–1024. doi: 10.1126/science.1096615. [DOI] [PubMed] [Google Scholar]
  • 54.Massey PV, Johnson BE, Moult PR, et al. Differential roles of NR2A and NR2B-containing NMDA receptors in cortical long-term potentiation and long-term depression. J Neurosci. 2004;24:7821–7828. doi: 10.1523/JNEUROSCI.1697-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 55.Morishita W, Lu W, Smith GB, Nicoll RA, Bear MF, Malenka RC. Activation of NR2B-containing NMDA receptors is not required for NMDA receptor-dependent long-term depression. Neuropharmacology. 2007;52:71–76. doi: 10.1016/j.neuropharm.2006.07.005. [DOI] [PubMed] [Google Scholar]
  • 56.Bartlett TE, Bannister NJ, Collett VJ, et al. Differential roles of NR2A and NR2B-containing NMDA receptors in LTP and LTD in the CA1 region of two-week old rat hippocampus. Neuropharmacology. 2007;52:60–70. doi: 10.1016/j.neuropharm.2006.07.013. [DOI] [PubMed] [Google Scholar]
  • 57.Frizelle PA, Chen PE, Wyllie DJ. Equilibrium constants for (R)-[(S)-1-(4-bromo-phenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid (NVP-AAM077) acting at recombinant NR1/NR2A and NR1/NR2B N-methyl-D-aspartate receptors: Implications for studies of synaptic transmission. Mol Pharmacol. 2006;70:1022–1032. doi: 10.1124/mol.106.024042. [DOI] [PubMed] [Google Scholar]
  • 58.Feng B, Tse HW, Skifter DA, Morley R, Jane DE, Monaghan DT. Structure—activity analysis of a novel NR2C/NR2D-preferring NMDA receptor antagonist: 1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid. Br J Pharmacol. 2004;141:508–516. doi: 10.1038/sj.bjp.0705644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Wu LJ, Xu H, Ren M, Cao X, Zhuo M. Pharmacological isolation of postsynaptic currents mediated by NR2A- and NR2B-containing NMDA receptors in the anterior cingulate cortex. Mol Pain. 2007;3:11–11. doi: 10.1186/1744-8069-3-11. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Hrabetova S, Serrano P, Blace N, et al. Distinct NMDA receptor subpopulations contribute to long-term potentiation and long-term depression induction. J Neurosci. 2000;20:RC81–RC81. doi: 10.1523/JNEUROSCI.20-12-j0002.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.Omote K, Kawamata T, Kawamata M, Namiki A. Formalin-induced release of excitatory amino acids in the skin of the rat hindpaw. Brain Res. 1998;787:161–164. doi: 10.1016/S0006-8993(97)01568-0. [DOI] [PubMed] [Google Scholar]
  • 62.Carlton SM, Coggeshall RE. Inflammation-induced changes in peripheral glutamate receptor populations. Brain Res. 1999;820:63–70. doi: 10.1016/S0006-8993(98)01328-6. [DOI] [PubMed] [Google Scholar]
  • 63.Wilson JA, Garry EM, Anderson HA, et al. 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. 2005;117:421–432. doi: 10.1016/j.pain.2005.07.005. [DOI] [PubMed] [Google Scholar]
  • 64.Burton AW, Lee DH, Saab C, Chung JM. Preemptive intrathecal ketamine injection produces a long-lasting decrease in neuropathic pain behaviors in a rat model. Reg Anesth Pain Med. 1999;24:208–213. doi: 10.1016/s1098-7339(99)90129-3. [DOI] [PubMed] [Google Scholar]
  • 65.South SM, Kohno T, Kaspar BK, et al. 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. 2003;23:5031–5040. doi: 10.1523/JNEUROSCI.23-12-05031.2003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.Petrenko AB, Yamakura T, Baba H, Sakimura K. Unaltered pain-related behavior in mice lacking NMDA receptor GluRε 1 subunit. Neurosci Res. 2003;46:199–204. doi: 10.1016/s0168-0102(03)00061-0. [DOI] [PubMed] [Google Scholar]
  • 67.Malmberg AB, Gilbert H, McCabe RT, Basbaum AI. Powerful antinociceptive effects of the cone snail venom-derived subtype-selective NMDA receptor antagonists conantokins G and T. Pain. 2003;101:109–116. doi: 10.1016/S0304-3959(02)00303-2. [DOI] [PubMed] [Google Scholar]
  • 68.Terayama R, Guan Y, Dubner R, Ren K. Activity-induced plasticity in brain stem pain modulatory circuitry after inflammation. Neuroreport. 2000;11:1915–1919. doi: 10.1097/00001756-200006260-00022. [DOI] [PubMed] [Google Scholar]
  • 69.Tang YP, Shimizu E, Dube GR, et al. Genetic enhancement of learning and memory in mice. Nature. 1999;401:63–69. doi: 10.1038/43432. [DOI] [PubMed] [Google Scholar]
  • 70.Quintero GC, Erzurumlu RS, Vaccarino AL. Decreased pain response in mice following cortex-specific knockout of the N-methyl-d-aspartate NR1 subunit. Neurosci Lett. 2007;425:89–93. doi: 10.1016/j.neulet.2007.08.030. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 71.Wu LJ, Toyoda H, Zhao MG, et al. Upregulation of forebrain NMDA NR2B receptors contributes to behavioral seusitization after inflammation. J Neurosci. 2005;25:11107–11016. doi: 10.1523/JNEUROSCI.1678-05.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 72.Shum FW, Wu LJ, Zhao MG, et al. Alteration of cingulate long-term plasticity and behavioral sensitization to inflammation by environmental enrichment. Learn Mem. 2007;14:304–312. doi: 10.1101/lm.530607. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 73.Xu H, Wu LJ, Wang H, et al. Presynaptic and postsynaptic amplifications of neuropathic pain in the anterior cingulate cortex. J Neurosci. 2008;28:7445–7453. doi: 10.1523/JNEUROSCI.1812-08.2008. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 74.Kristensen JD, Svensson B, Gordh T. The, NMDA-receptor antagonist CPP abolishes neurogenic ‘wind-up pain’ after intrathecal administration in humans. Pain. 1992;51:249–253. doi: 10.1016/0304-3959(92)90266-E. [DOI] [PubMed] [Google Scholar]
  • 75.Brandt MR, Cummons TA, Potestio L, Sukoff SJ, Rosenzweig-Lipson S. Effects of the N-methyl-d-aspartate receptor antagonist perzinfotel [EAA-090;[2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid] on chemically induced thermal hypersensitivity. J Pharmacol Exp Ther. 2005;313:1379–1386. doi: 10.1124/jpet.105.084467. [DOI] [PubMed] [Google Scholar]
  • 76.Baudy RB, Butera JA, Abou-Gharbia MA, et al. Prodrugs of perzinfotel with improved oral bioavailability. J Med Chem. 2009;52:771–778. doi: 10.1021/jm8011799. [DOI] [PubMed] [Google Scholar]
  • 77.Chizh BA, Headley PM. NMDA antagonists and neuropathic pain: multiple drug targets and multiple uses. Curr Pharm Des. 2005;11:2977–2994. doi: 10.2174/1381612054865082. [DOI] [PubMed] [Google Scholar]
  • 78.Hocking G, Cousins M.T. Ketarmne in chronic pain management: an evidence-based review. Anesth Analg. 2003;97:1730–1739. doi: 10.1213/01.ANE.0000086618.28845.9B. [DOI] [PubMed] [Google Scholar]
  • 79.Mathisen LC, Skjelbred P, Skoglund LA, Oye I. Effect of ketamine, an NMDA receptor inhibitor, in acute and chronic orofacial pain. Pain. 1995;61:215–220. doi: 10.1016/0304-3959(94)00170-J. [DOI] [PubMed] [Google Scholar]
  • 80.Nelson KA, Park KM, Robinovitz E, Tsigos C, Max MB. High-dose oral dextromethorphan versus placebo in painful diabetic neuropathy and postherpetic neuralgia. Neurology. 1997;48:1212–1218. doi: 10.1212/wnl.48.5.1212. [DOI] [PubMed] [Google Scholar]
  • 81.Sang CN, Booher S, Gilron I, Parada S, Max MB. Dextromethorphan and memantine in painful diabetic neuropathy and postherpetic neuralgia: efficacy and dose-response trials. Anesthesiology. 2002;96:1053–1061. doi: 10.1097/00000542-200205000-00005. [DOI] [PubMed] [Google Scholar]
  • 82.Pud D, Eisenberg E, Spitzer A, et al. The NMDA receptor antagonist amantadine reduces surgical neuropathic pain in cancer patients: a double blind, randomized, placebo controlled trial. Pain. 1998;75:349–354. doi: 10.1016/S0304-3959(98)00014-1. [DOI] [PubMed] [Google Scholar]
  • 83.Gurwitz D, Weizman A. The NR2B subunit of glutamate receptors as a potential target for relieving chronic pain: prospects and concerns. Drug Discov Today. 2002;7:403–406. doi: 10.1016/S1359-6446(02)02242-0. [DOI] [PubMed] [Google Scholar]
  • 84.Ko SW, Wu LJ, Shum F, Quan J, Zhuo M. Cingulate NMDA NR2B receptors contribute to morphine-induced analgesic tolerance. Mol Brain. 2008;1:2–2. doi: 10.1186/1756-6606-1-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 85.Narita M, Aoki T, Suzuki T. Molecular evidence for the involvement of NR2B subunit containing N-methyl-d-aspartate receptors in the development of morphine-induced place preference. Neuroscience. 2000;101:601–606. doi: 10.1016/S0306-4522(00)00405-X. [DOI] [PubMed] [Google Scholar]
  • 86.Nakazato E, Kato A, Watanabe S. Brain but not spinal NR2B receptor is responsible for the anti-allodynic effect of an NR2B subunit-selective antagonist CP-101,606 in a rat chronic constriction injury model. Pharmacology. 2005;73:8–14. doi: 10.1159/000081069. [DOI] [PubMed] [Google Scholar]
  • 87.Hutchison WD, Davis KD, Lozano AM, Tasker RR, Dostrovsky JO. Pain-related neurons in the human cingulate cortex. Nat Neurosci. 1999;2:403–405. doi: 10.1038/8065. [DOI] [PubMed] [Google Scholar]
  • 88.Köhr G. NMDA receptor function: subunit composition versus spatial distribution. Cell Tissue Res. 2006;326:439–446. doi: 10.1007/s00441-006-0273-6. [DOI] [PubMed] [Google Scholar]

Articles from Neurotherapeutics are provided here courtesy of Elsevier

RESOURCES