Changes in NK1 and Glutamate Receptors in Pain

  • Andrew J. Todd


The amino acid glutamate and the neuropeptide substance P are contained in many nociceptive primary afferents that terminate mainly in the superficial part of the dorsal horn. Both glutamate and substance P are released from the central terminals of nociceptive afferents following noxious stimulation. Glutamate acts on a variety of ionotropic and metabotropic receptors, while substance P acts on the neurokinin 1 receptor (NK1r), and both transmitters contribute to the processing of nociceptive information at the spinal level. Noxious stimulation of the hindpaw causes rapid (within minutes) internalisation of the NK1r, phosphorylation of the GluR1 subunit of the AMPA-type glutamate receptor and phosphorylation of the NR1 subunit of NMDA-type glutamate receptors. These plastic changes of SP and glutamate receptors that occur in acute and chronic pain states presumably contribute to sensitisation of dorsal horn neurons (central sensitization).


Dorsal Horn Projection Neuron Dorsal Horn Neuron Spinal Nerve Ligation Noxious Stimulation 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.



α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanic acid


calcitonin gene related peptide


complete Freund’s adjuvant


caudal ventrolateral medulla


dorsal root ganglion


lateral parabrachial area


long term potentiation


neurokinin 1 receptor




periaqueductal grey


  1. Abbadie C, Brown JL, Mantyh PW et al (1996) Spinal cord substance P receptor immunoreactivity increases in both inflammatory and nerve injury models of persistent pain. Neuroscience 70:201–209PubMedCrossRefGoogle Scholar
  2. Abbadie C, Trafton J, Liu H et al (1997) Inflammation increases the distribution of dorsal horn neurons that internalize the neurokinin-1 receptor in response to noxious and non-noxious stimulation. J Neurosci 17:8049–8060PubMedGoogle Scholar
  3. Abe T, Matsumura S, Katano T et al (2005) Fyn kinase-mediated phosphorylation of NMDA receptor NR2B subunit at Tyr1472 is essential for maintenance of neuropathic pain. Eur J Neurosci 22:1445–1454PubMedCrossRefGoogle Scholar
  4. Al-Khater KM, Kerr R, Todd AJ (2008) A quantitative study of spinothalamic neurons in laminae I, III and IV in lumbar and cervical segments of the rat spinal cord. J Comp Neurol 511:1–18Google Scholar
  5. Allen BJ, Li J, Menning PM, Rogers SD et al (1999) Primary afferent fibers that contribute to increased substance P receptor internalization in the spinal cord after injury. J Neurophysiol 81:1379–1390PubMedGoogle Scholar
  6. Alvarez FJ, Villalba RM, Carr PA et al (2000) Differential distribution of metabotropic glutamate receptors 1a, 1b, and 5 in the rat spinal cord. J Comp Neurol 422:464–487PubMedCrossRefGoogle Scholar
  7. Alvarez FJ, Villalba RM, Zerda R et al (2004) Vesicular glutamate transporters in the spinal cord, with special reference to sensory primary afferent synapses. J Comp Neurol 472:257–280PubMedCrossRefGoogle Scholar
  8. Azkue JJ, Murga M, Fernandez-Capetillo O et al (2001) Immunoreactivity for the group III metabotropic glutamate receptor subtype mGluR4a in the superficial laminae of the rat spinal dorsal horn. J Comp Neurol 430:448–457PubMedCrossRefGoogle Scholar
  9. Bleazard L, Hill RG, Morris R (1994) The correlation between the distribution of the NK1 receptor and the actions of tachykinin agonists in the dorsal horn of the rat indicates that substance P does not have a functional role on substantia gelatinosa (lamina II) neurons. J Neurosci 14:7655–7664PubMedGoogle Scholar
  10. Boxall SJ, Berthele A, Laurie DJ et al (1998) Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation. Neuroscience 82:591–602PubMedCrossRefGoogle Scholar
  11. 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 20:375–384PubMedCrossRefGoogle Scholar
  12. 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 5:1050–1061PubMedCrossRefGoogle Scholar
  13. Broman J (1994) Neurotransmitters in subcortical somatosensory pathways. Anat Embryol (Berl) 189:181–214CrossRefGoogle Scholar
  14. Brown JL, Liu H, Maggio JE et al (1995) Morphological characterization of substance P receptor-immunoreactive neurons in the rat spinal cord and trigeminal nucleus caudalis. J Comp Neurol 356:327–344PubMedCrossRefGoogle Scholar
  15. Caudle RM, Perez FM, Valle-Pinero AY et al (2005) Spinal cord NR1 serine phosphorylation and NR2B subunit suppression following peripheral inflammation. Mol Pain 1:25PubMedCrossRefGoogle Scholar
  16. Chen BS, Roche KW (2007) Regulation of NMDA receptors by phosphorylation. Neuropharmacology 53:362–368PubMedCrossRefGoogle Scholar
  17. Cheunsuang O, Morris R (2000) Spinal lamina I neurons that express neurokinin 1 receptors: morphological analysis. Neuroscience 97:335–345PubMedCrossRefGoogle Scholar
  18. De Biasi S, Rustioni A (1988) Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord. Proc Natl Acad Sci USA 85:7820–7824PubMedCrossRefGoogle Scholar
  19. Ding YQ, Takada M, Shigemoto R et al (1995) Spinoparabrachial tract neurons showing substance P receptor-like immunoreactivity in the lumbar spinal cord of the rat. Brain Res 674:336–340PubMedCrossRefGoogle Scholar
  20. Dolan S, Kelly JG, Monteiro AM et al (2003) Up-regulation of metabotropic glutamate receptor subtypes 3 and 5 in spinal cord in a clinical model of persistent inflammation and hyperalgesia. Pain 106:501–512PubMedCrossRefGoogle Scholar
  21. Dolan S, Kelly JG, Monteiro AM et al (2004) Differential expression of central metabotropic glutamate receptor (mGluR) subtypes in a clinical model of post-surgical pain. Pain 110:369–377PubMedCrossRefGoogle Scholar
  22. 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
  23. Fang L, Wu J, Zhang X, Lin Q, et al (2003) 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 122:237–245PubMedCrossRefGoogle Scholar
  24. Furuyama T, Kiyama H, Sato K et al (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 18:141–151PubMedCrossRefGoogle Scholar
  25. 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 112:315–323PubMedCrossRefGoogle Scholar
  26. Gao X, Kim HK, Chung JM et al (2005) Enhancement of NMDA receptor phosphorylation of the spinal dorsal horn and nucleus gracilis neurons in neuropathic rats. Pain 116:62–72PubMedCrossRefGoogle Scholar
  27. Garry EM, Moss A, Rosie R et al (2003) Specific involvement in neuropathic pain of AMPA receptors and adapter proteins for the GluR2 subunit. Mol Cell Neurosci 24:10–22PubMedCrossRefGoogle Scholar
  28. Goff JR, Burkey AR, Goff DJ et al (1998) Reorganization of the spinal dorsal horn in models of chronic pain: correlation with behaviour. Neuroscience 82:559–574PubMedCrossRefGoogle Scholar
  29. Guo W, Zou S, Guan Y et al (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
  30. Harris JA, Corsi M, Quartaroli M et al (1996) Upregulation of spinal glutamate receptors in chronic pain. Neuroscience 74:7–12PubMedCrossRefGoogle Scholar
  31. Hokfelt T, Ljungdahl A, Terenius L et al (1977) Immunohistochemical analysis of peptide pathways possibly related to pain and analgesia: enkephalin and substance P. Proc Natl Acad Sci USA 74:3081–3085PubMedCrossRefGoogle Scholar
  32. Honore P, Menning PM, Rogers SD et al (1999) Spinal substance P receptor expression and internalization in acute, short-term, and long-term inflammatory pain states. J Neurosci 19:7670–7678Google Scholar
  33. Honoré P, Kamp EH, Rogers SD et al (2002) Activation of lamina I spinal cord neurons that express the substance P receptor in visceral nociception and hyperalgesia. J Pain 3:3–11.Google Scholar
  34. Hudson LJ, Bevan S, McNair K et al (2002) Metabotropic glutamate receptor 5 upregulation in A-fibers after spinal nerve injury: 2-methyl-6-(phenylethynyl)-pyridine (MPEP) reverses the induced thermal hyperalgesia. J Neurosci 22:2660–2668PubMedGoogle Scholar
  35. Jakowec MW, Fox AJ, Martin LJ et al (1995) Quantitative and qualitative changes in AMPA receptor expression during spinal cord development. Neuroscience 67:893–907PubMedCrossRefGoogle Scholar
  36. Jia H, Rustioni A, Valtschanoff JG (1999) Metabotropic glutamate receptors in superficial laminae of the rat dorsal horn. J Comp Neurol 410:627–642PubMedCrossRefGoogle Scholar
  37. Ju G, Hokfelt T, Brodin E et al (1987) Primary sensory neurons of the rat showing calcitonin gene-related peptide immunoreactivity and their relation to substance P-, somatostatin-, galanin-, vasoactive intestinal polypeptide- and cholecystokinin-immunoreactive ganglion cells. Cell Tissue Res 247:417–431PubMedCrossRefGoogle Scholar
  38. Lawson SN, Crepps BA, Perl ER (1997) Relationship of substance P to afferent characteristics of dorsal root ganglion neurones in guinea-pig. J Physiol 505 (Pt 1):177–191PubMedCrossRefGoogle Scholar
  39. Li JL, Ding YQ, Xiong KH et al (1998) Substance P receptor (NK1)-immunoreactive neurons projecting to the periaqueductal gray: distribution in the spinal trigeminal nucleus and the spinal cord of the rat. Neurosci Res 30:219–225PubMedCrossRefGoogle Scholar
  40. Littlewood NK, Todd AJ, Spike RC et al (1995) The types of neuron in spinal dorsal horn which possess neurokinin-1 receptors. Neuroscience 66:597–608PubMedCrossRefGoogle Scholar
  41. Liu H, Brown JL, Jasmin L et al (1994) Synaptic relationship between substance P and the substance P receptor: light and electron microscopic characterization of the mismatch between neuropeptides and their receptors. Proc Natl Acad Sci USA 91:1009–1013PubMedCrossRefGoogle Scholar
  42. Mantyh PW, DeMaster E, Malhotra A et al (1995) Receptor endocytosis and dendrite reshaping in spinal neurons after somatosensory stimulation. Science 268:1629–1632PubMedCrossRefGoogle Scholar
  43. Marshall GE, Shehab SA, Spike RC et al (1996) Neurokinin-1 receptors on lumbar spinothalamic neurons in the rat. Neuroscience 72:255–263PubMedCrossRefGoogle Scholar
  44. McCarson KE, Krause JE (1994) NK-1 and NK-3 type tachykinin receptor mRNA expression in the rat spinal cord dorsal horn is increased during adjuvant or formalin-induced nociception. J Neurosci 14:712–720PubMedGoogle Scholar
  45. Nagy GG, Al Ayyan M, Andrew D et al (2004a) 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 24:5766–5777PubMedCrossRefGoogle Scholar
  46. Nagy GG, Watanabe M, Fukaya M et al (2004b) 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 20:3301–3312PubMedCrossRefGoogle Scholar
  47. Naim M, Spike RC, Watt C et al (1997) Cells in laminae III and IV of the rat spinal cord that possess the neurokinin-1 receptor and have dorsally directed dendrites receive a major synaptic input from tachykinin-containing primary afferents. J Neurosci 17:5536–5548PubMedGoogle Scholar
  48. Nakaya Y, Kaneko T, Shigemoto R et al (1994) Immunohistochemical localization of substance P receptor in the central nervous system of the adult rat. J Comp Neurol 347:249–274PubMedCrossRefGoogle Scholar
  49. Ohishi H, Nomura S, Ding YQ et al (1995) Presynaptic localization of a metabotropic glutamate receptor, mGluR7, in the primary afferent neurons: an immunohistochemical study in the rat. Neurosci Lett 202:85–88PubMedCrossRefGoogle Scholar
  50. Oliveira AL, Hydling F, Olsson E et al (2003) Cellular localization of three vesicular glutamate transporter mRNAs and proteins in rat spinal cord and dorsal root ganglia. Synapse 50:117–129PubMedCrossRefGoogle Scholar
  51. Palecek J, Paleckova V, Willis WD (2003) Postsynaptic dorsal column neurons express NK1 receptors following colon inflammation. Neuroscience 116:565–572PubMedCrossRefGoogle Scholar
  52. Pezet S, Marchand F, D'Mello R et al (2008) Phosphatidylinositol 3-kinase is a key mediator of central sensitization in painful inflammatory conditions. J Neurosci 28:4261–4270PubMedCrossRefGoogle Scholar
  53. Pitcher MH, Ribeiro-da-Silva A, Coderre TJ (2007) Effects of inflammation on the ultrastructural localization of spinal cord dorsal horn group I metabotropic glutamate receptors. J Comp Neurol 505:412–423PubMedCrossRefGoogle Scholar
  54. Polgar E, Shehab SA, Watt C et al (1999) GABAergic neurons that contain neuropeptide Y selectively target cells with the neurokinin 1 receptor in laminae III and IV of the rat spinal cord. J Neurosci 19:2637–2646PubMedGoogle Scholar
  55. Polgar E, Puskar Z, Watt C et al (2002) Selective innervation of lamina I projection neurones that possess the neurokinin 1 receptor by serotonin-containing axons in the rat spinal cord. Neuroscience 109:799–809PubMedCrossRefGoogle Scholar
  56. Polgar E, Hughes DI, Riddell JS et al (2003) Selective loss of spinal GABAergic or glycinergic neurons is not necessary for development of thermal hyperalgesia in the chronic constriction injury model of neuropathic pain. Pain 104:229–239PubMedCrossRefGoogle Scholar
  57. Polgár E, Campbell A, MacIntyre LM et al (2007) Phosphorylation of ERK in neurokinin 1 receptor-expressing neurons in laminae III and IV of the rat spinal dorsal horn following noxious stimulation. Mol Pain 3:4PubMedCrossRefGoogle Scholar
  58. Polgar E, Watanabe M, Hartmann B et al (2008) Expression of AMPA receptor subunits at synapses in laminae I–III of the rodent spinal dorsal horn. Mol Pain 4:5PubMedCrossRefGoogle Scholar
  59. Popratiloff A, Weinberg RJ, Rustioni A (1996) AMPA receptor subunits underlying terminals of fine-caliber primary afferent fibers. J Neurosci 16:3363–3372PubMedGoogle Scholar
  60. Popratiloff A, Weinberg RJ, Rustioni A (1998) AMPA receptors at primary afferent synapses in substantia gelatinosa after sciatic nerve section. Eur J Neurosci 10:3220–3230PubMedCrossRefGoogle Scholar
  61. Prybylowski KL, Grossman SD, Wrathall JR et al (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 76:797–805PubMedCrossRefGoogle Scholar
  62. Rexed B (1954) A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol 100:297–379PubMedCrossRefGoogle Scholar
  63. Ribeiro-da-Silva A, de Koninck Y (2008) Morphological and neurochemical organization of the spinal dorsal horn. In: Bushnell MC, Basbaum AI (eds). Pain, Academic Press, San DiegoGoogle Scholar
  64. Sakamoto H, Spike RC, Todd AJ (1999) Neurons in laminae III and IV of the rat spinal cord with the neurokinin-1 receptor receive few contacts from unmyelinated primary afferents which do not contain substance P. Neuroscience 94:903–908PubMedCrossRefGoogle Scholar
  65. Schafer MK, Nohr D, Krause JE et al (1993) Inflammation-induced upregulation of NK1 receptor mRNA in dorsal horn neurones. Neuroreport 4:1007–1010PubMedCrossRefGoogle Scholar
  66. Scott DB, Blanpied TA, Ehlers MD (2003) Coordinated PKA and PKC phosphorylation suppresses RXR-mediated ER retention and regulates the surface delivery of NMDA receptors. Neuropharmacology 45:755–767PubMedCrossRefGoogle Scholar
  67. Spike RC, Puskar Z, Andrew D et al (2003) A quantitative and morphological study of projection neurons in lamina I of the rat lumbar spinal cord. Eur J Neurosci 18:2433–2448PubMedCrossRefGoogle Scholar
  68. Tachibana M, Wenthold RJ, Morioka H et al (1994) Light and electron microscopic immunocytochemical localization of AMPA-selective glutamate receptors in the rat spinal cord. J Comp Neurol 344:431–454PubMedCrossRefGoogle Scholar
  69. Todd AJ, Spike RC, Polgar E (1998) A quantitative study of neurons which express neurokinin-1 or somatostatin sst2a receptor in rat spinal dorsal horn. Neuroscience 85:459–473PubMedCrossRefGoogle Scholar
  70. Todd AJ, McGill MM, Shehab SA (2000) Neurokinin 1 receptor expression by neurons in laminae I, III and IV of the rat spinal dorsal horn that project to the brainstem. Eur J Neurosci 12:689–700PubMedCrossRefGoogle Scholar
  71. 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 87:245–249PubMedCrossRefGoogle Scholar
  72. Todd AJ, Puskar Z, Spike RC et al (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
  73. Todd AJ, Hughes DI, Polgar E et al (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 17:13–27PubMedCrossRefGoogle Scholar
  74. Todd AJ, Koerber HR (2005) Neuroanatomical substrates of spinal nociception. In: McMahon S, Koltzenburg M (eds) Melzack and Wall's textbook of pain, Churchill Linvingstone, EdinburghGoogle Scholar
  75. Todd AJ, Ribeiro-da-Silva A (2007) Anatomical changes in the spinal dorsal horn after peripheral nerve injury. In Zhuo M (ed) Molecular Pain, Beijing Higher Education Press/Springer, BeijingGoogle Scholar
  76. Todd AJ (2008) Neuronal circuits and receptors involved in spinal cord pain processing. In Castro-Lopes M (ed) Current topics in pain: 12th World Congress on Pain, IASP Press, SeattleGoogle Scholar
  77. Tölle TR, Berthele A, Zieglgansberger W et al (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
  78. Tong CK, MacDermott AB (2006) Both Ca2+-permeable and -impermeable AMPA receptors contribute to primary synaptic drive onto rat dorsal horn neurons. J Physiol 575:133–144PubMedCrossRefGoogle Scholar
  79. Vidnyánszky Z, Hámori J, Negyessy L (1994) Cellular and subcellular localization of the mGluR5a metabotropic glutamate receptor in rat spinal cord. Neuroreport 6:209–213PubMedCrossRefGoogle Scholar
  80. Walker K, Reeve A, Bowes M (2001) mGlu5 receptors and nociceptive function II. mGlu5 receptors functionally expressed on peripheral sensory neurones mediate inflammatory hyperalgesia. Neuropharmacology 40:10–19PubMedCrossRefGoogle Scholar
  81. Warden MK, Young WS III (1988) Distribution of cells containing mRNAs encoding substance P and neurokinin B in the rat central nervous system. J Comp Neurol 272:90–113PubMedCrossRefGoogle Scholar
  82. Watanabe M, Mishina M, Inoue Y (1994) Distinct spatiotemporal distributions of the N-methyl-D-aspartate receptor channel subunit mRNAs in the mouse cervical cord. J Comp Neurol 345:314–319PubMedCrossRefGoogle Scholar
  83. Yang L, Zhang FX, Huang F et al (2004) Peripheral nerve injury induces trans-synaptic modification of channels, receptors and signal pathways in rat dorsal spinal cord. Eur J Neurosci 19:871–883Google Scholar
  84. Zhang X, Wu J, Lei Y et al (2005) Protein phosphatase modulates the phosphorylation of spinal cord NMDA receptors in rats following intradermal injection of capsaicin. Brain Res Mol Brain Res 138:264–272PubMedCrossRefGoogle Scholar
  85. Zhou QQ, Imbe H, Zou S et al (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 88:186–193PubMedCrossRefGoogle Scholar
  86. 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

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Institute of Biomedical and Life SciencesUniversity of GlasgowGlasgowUK

Personalised recommendations