Skip to main content
Springer Nature Link
Log in

AMPA and NMDA glutamate receptors are found in both peptidergic and non-peptidergic primary afferent neurons in the rat

  • Regular Article
  • Published:
Cell and Tissue Research Aims and scope Submit manuscript

Abstract

Two distinct classes of nociceptive primary afferents, peptidergic and non-peptidergic, respond similarly to acute noxious stimulation; however the peptidergic afferents are more likely to play a role in inflammatory pain, while the non-peptidergic afferents may be more characteristically involved in neuropathic pain. Using multiple immunofluorescence, we determined the proportions of neurons in the rat L4 dorsal root ganglion (DRG) that co-express AMPA or NMDA glutamate receptors and markers for the peptidergic and non-peptidergic classes of primary afferents, substance P and P2X3, respectively. The fraction of DRG neurons immunostained for the NR1 subunit of the NMDA receptor (40%) was significantly higher than that of DRG neurons immunostained for the GluR2/3 (27%) or the GluR4 (34%) subunits of the AMPA receptor. Of all DRG neurons double-immunostained for glutamate receptor subunits and either marker for peptidergic and non-peptidergic afferents, a significantly larger proportion expressed GluR4 than GluR2/3 or NR1 and in a significantly larger proportion of P2X3- than SP-positive DRG neurons. These observations support the idea that nociceptors, involved primarily in the mediation of neuropathic pain, may be presynaptically modulated by GluR4-containing AMPA receptors.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+
from $39.99 /Month
  • Starting from 10 chapters or articles per month
  • Access and download chapters and articles from more than 300k books and 2,500 journals
  • Cancel anytime
View plans

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Explore related subjects

Discover the latest articles, books and news in related subjects, suggested using machine learning.

References

  • Bae YC, Oh JM, Hwang SJ, Shigenaga Y, Valtschanoff JG (2004) Expression of vanilloid receptor TRPV1 in the rat trigeminal sensory nuclei. J Comp Neurol 478:62–71

    Article  PubMed  CAS  Google Scholar 

  • 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 24:2774–2781

    Article  PubMed  CAS  Google Scholar 

  • Battaglia G, Rustioni A (1988) Coexistence of glutamate and substance P in dorsal root ganglion neurons of the rat and monkey. J Comp Neurol 277:302–312

    Article  PubMed  CAS  Google Scholar 

  • Bennett DL, Averill S, Clary DO, Priestley JV, McMahon SB (1996) Postnatal changes in the expression of the trkA high-affinity NGF receptor in primary sensory neurons. Eur J Neurosci 8:2204–2208

    Article  PubMed  CAS  Google Scholar 

  • Bergman E, Carlsson K, Liljeborg A, Manders E, Hökfelt T, Ulfhake B (1999) Neuropeptides, nitric oxide synthase and GAP-43 in B4-binding and RT97 immunoreactive primary sensory neurons: normal distribution pattern and changes after peripheral nerve transection and aging. Brain Res 832:63–83

    Article  PubMed  CAS  Google Scholar 

  • Bleakman D, Alt A, Nisenbaum ES (2006) Glutamate receptors and pain. Semin Cell Dev Biol 17:592–604

    Article  PubMed  CAS  Google Scholar 

  • Bradbury EJ, Burnstock G, McMahon SB (1998) The expression of P2X3 purinoreceptors in sensory neurons: effects of axotomy and glial-derived neurotrophic factor. Mol Cell Neurosci 12:256–268

    Article  PubMed  CAS  Google Scholar 

  • Brumovsky P, Watanabe M, Hökfelt T (2007) Expression of the vesicular glutamate transporters-1 and -2 in adult mouse dorsal root ganglia and spinal cord and their regulation by nerve injury. Neuroscience 147:469–490

    Article  PubMed  CAS  Google Scholar 

  • Carlton SM, Hargett GL (2002) Stereological analysis of Ca(2+)/calmodulin-dependent protein kinase II alpha -containing dorsal root ganglion neurons in the rat: colocalization with isolectin Griffonia simplicifolia, calcitonin gene-related peptide, or vanilloid receptor 1. J Comp Neurol 448:102–110

    Article  PubMed  CAS  Google Scholar 

  • Carlton SM, Hargett GL, Coggeshall RE (1995) Localization and activation of glutamate receptors in unmyelinated axons of rat glabrous skin. Neurosci Lett 197:25–28

    Article  PubMed  CAS  Google Scholar 

  • Chambille I, Rampin O (2002) AMPA glutamatergic receptor-immunoreactive subunits are expressed in lumbosacral neurons of the spinal cord and neurons of the dorsal root and pelvic ganglia controlling pelvic functions in the rat. Brain Res 933:66–80

    Article  PubMed  CAS  Google Scholar 

  • Coggeshall RE (1992) A consideration of neural counting methods. Trends Neurosci 15:9–13

    Article  PubMed  CAS  Google Scholar 

  • Fukuoka T, Tokunaga A, Tachibana T, Dai Y, Yamanaka H, Noguchi K (2002) VR1, but not P2X(3), increases in the spared L4 DRG in rats with L5 spinal nerve ligation. Pain 99:111–120

    Article  PubMed  CAS  Google Scholar 

  • Hökfelt T, Kellerth JO, Nilsson G, Pernow B (1975) Experimental immunohistochemical studies on the localization and distribution of substance P in cat primary sensory neurons. Brain Res 100:235–252

    Article  PubMed  Google Scholar 

  • Hunt SP, Rossi J (1985) Peptide- and non-peptide-containing unmyelinated primary afferents: the parallel processing of nociceptive information. Philos Trans R Soc Lond B Biol Sci 308:283–289

    Article  PubMed  CAS  Google Scholar 

  • Hunt SP, Mantyh PW (2001) The molecular dynamics of pain control. Nat Rev Neurosci 2:83–91

    Article  PubMed  CAS  Google Scholar 

  • Hwang SJ, Pagliardini S, Rustioni A, Valtschanoff JG (2001a) Presynaptic kainate receptors in primary afferents to the superficial laminae of the rat spinal cord. J Comp Neurol 436:275–289

    Article  PubMed  CAS  Google Scholar 

  • Hwang SJ, Rustioni A, Valtschanoff JG (2001b) Kainate receptors in primary afferents to the rat gracile nucleus. Neurosci Lett 312:137–140

    Article  PubMed  CAS  Google Scholar 

  • Hwang SJ, Oh JM, Valtschanoff JG (2005) The majority of bladder sensory afferents to the rat lumbosacral spinal cord are both IB4- and CGRP-positive. Brain Res 1062:86–91

    Article  PubMed  CAS  Google Scholar 

  • Jia H, Rustioni A, Valtschanoff JG (1999) Metabotropic glutamate receptors in superficial laminae of the rat dorsal horn. J Comp Neurol 410:627–642

    Article  PubMed  CAS  Google Scholar 

  • Julius D, Basbaum AI (2001) Molecular mechanisms of nociception. Nature 413:203–210

    Article  PubMed  CAS  Google Scholar 

  • Kashiba H, Uchida Y, Senba E (2001) Difference in binding by isolectin B4 to trkA and c-ret mRNA-expressing neurons in rat sensory ganglia. Brain Res Mol Brain Res 95:18–26

    Article  PubMed  CAS  Google Scholar 

  • Kim YS, Paik SK, Cho YS, Shin HS, Bae JY, Moritani M, Yoshida A, Ahn DK, Valtschanoff J, Hwang SJ, Moon C, Bae YC (2008) Expression of P2X3 receptor in the trigeminal sensory nuclei of the rat. J Comp Neurol 506:627–639

    Article  PubMed  CAS  Google Scholar 

  • Lawson SN, Crepps BA, Perl ER (1997) Relationship of substance P to afferent characteristics of dorsal root ganglion neurones in guinea-pig. J Physiol 505:177–191

    Article  PubMed  CAS  Google Scholar 

  • Lee CJ, Bardoni R, Tong CK, Engelman HS, Joseph DJ, Magherini PC, MacDermott AB (2002) Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release. Neuron 35:135–146

    Article  PubMed  CAS  Google Scholar 

  • Light AR, Perl ER (2003) Unmyelinated afferent fibers are not only for pain anymore. J Comp Neurol 461:137–139

    Article  PubMed  Google Scholar 

  • 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 91:8383–8387

    Article  PubMed  CAS  Google Scholar 

  • Liu H, Mantyh PW, Basbaum AI (1997) NMDA-receptor regulation of substance P release from primary afferent nociceptors. Nature 386:721–724

    Article  PubMed  CAS  Google Scholar 

  • Lu CR, Hwang SJ, Phend KD, Rustioni A, Valtschanoff JG (2002) Primary afferent terminals in spinal cord express presynaptic AMPA receptors. J Neurosci 22:9522–9529

    PubMed  CAS  Google Scholar 

  • 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 460:191–202

    Article  PubMed  CAS  Google Scholar 

  • 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 120:97–105

    Article  PubMed  CAS  Google Scholar 

  • Malcangio M, Fernandes K, Tomlinson DR (1998) NMDA receptor activation modulates evoked release of substance P from rat spinal cord. Br J Pharmacol 125:1625–1626

    Article  PubMed  CAS  Google Scholar 

  • Malmberg AB, Chen C, Tonegawa S, Basbaum AI (1997) Preserved acute pain and reduced neuropathic pain in mice lacking PKCgamma. Science 278:279–283

    Article  PubMed  CAS  Google Scholar 

  • Marvizón JC, Martinez V, Grady EF, Bunnett NW, Mayer EA (1997) Neurokinin 1 receptor internalization in spinal cord slices induced by dorsal root stimulation is mediated by NMDA receptors. J Neurosci 17:8129–8136

    PubMed  Google Scholar 

  • Marvizón 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 446:325–341

    Article  PubMed  Google Scholar 

  • Molliver DC, Wright DE, Leitner ML, Parsadanian AS, Doster K, Wen D, Yan Q, Snider WD (1997) IB4-binding DRG neurons switch from NGF to GDNF dependence in early postnatal life. Neuron 19:849–861

    Article  PubMed  CAS  Google Scholar 

  • Nichols ML, Allen BJ, Rogers SD, Ghilardi JR, Honore P, Luger NM, Finke MP, Li J, Lappi DA, Simone DA, Mantyh PW (1999) Transmission of chronic nociception by spinal neurons expressing the substance P receptor. Science 286:1558–1561

    Article  PubMed  CAS  Google Scholar 

  • Novakovic SD, Kassotakis LC, Oglesby IB, Smith JA, Eglen RM, Ford AP, Hunter JC (1999) Immunocytochemical localization of P2X3 purinoceptors in sensory neurons in naive rats and following neuropathic injury. Pain 80:273–282

    Article  PubMed  CAS  Google Scholar 

  • Nunzi MG, Pisarek A, Mugnaini E (2004) Merkel cells, corpuscular nerve endings and free nerve endings in the mouse palatine mucosa express three subtypes of vesicular glutamate transporters. J Neurocytol 33:359–376

    Article  PubMed  CAS  Google Scholar 

  • 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 8:263–272

    Article  PubMed  CAS  Google Scholar 

  • Sato K, Kiyama H, Park HT, Tohyama M (1993) AMPA, KA and NMDA receptors are expressed in the rat DRG neurones. Neuroreport 4:1263–1265

    Article  PubMed  CAS  Google Scholar 

  • Silverman JD, Kruger L (1990) Selective neuronal glycoconjugate expression in sensory and autonomic ganglia: relation of lectin reactivity to peptide and enzyme markers. J Neurocytol 19:789–801

    Article  PubMed  CAS  Google Scholar 

  • Stucky CL, Lewin GR (1999) Isolectin B(4)-positive and -negative nociceptors are functionally distinct. J Neurosci 19:6497–6505

    PubMed  CAS  Google Scholar 

  • Vulchanova L, Riedl MS, Shuster SJ, Stone LS, Hargreaves KM, Buell G, Surprenant A, North RA, Elde R (1998) P2X3 is expressed by DRG neurons that terminate in inner lamina II. Eur J Neurosci 10:3470–3478

    Article  PubMed  CAS  Google Scholar 

  • Wang H, Rivero-Melian C, Robertson B, Grant G (1994) Transganglionic transport and binding of the isolectin B4 from Griffonia simplicifolia I in rat primary sensory neurons. Neuroscience 62:539–551

    Article  PubMed  CAS  Google Scholar 

  • 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 265:195–198

    Article  PubMed  CAS  Google Scholar 

  • Willis WD, Coggeshall RE (2004) Sensory mechanisms of the spinal cord. Plenum, New York

    Google Scholar 

  • Zylka MJ, Rice FL, Anderson DJ (2005) Topographically distinct epidermal nociceptive circuits revealed by axonal tracers targeted to Mrgprd. Neuron 45:17–25

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

We thank Dr. A. Rustioni for support of this research and Dr. Lyndon M. Foster (Millipore Corporation, Temecula, CA) for expert technical assistance with the glutamate receptor antibodies.

Author information

Authors and Affiliations

  1. Department of Cell and Developmental Biology, University of North Carolina, CB# 7090, Chapel Hill, NC, 27599, USA

    Helen Willcockson & Juli Valtschanoff

Authors
  1. Helen Willcockson
    View author publications

    Search author on:PubMed Google Scholar

  2. Juli Valtschanoff
    View author publications

    Search author on:PubMed Google Scholar

Corresponding author

Correspondence to Helen Willcockson.

Additional information

Financial support for his work was provided by The National Institutes of Health, USA, through research grants NINDS12440 and AR053721.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Willcockson, H., Valtschanoff, J. AMPA and NMDA glutamate receptors are found in both peptidergic and non-peptidergic primary afferent neurons in the rat. Cell Tissue Res 334, 17–23 (2008). https://doi.org/10.1007/s00441-008-0662-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00441-008-0662-0

Keywords