Immunoreactivity for the group III metabotropic glutamate receptor subtype mGluR4a in the superficial laminae of the rat spinal dorsal horn

Studies indicate that metabotropic glutamate receptors (mGluRs) may play a role in spinal sensory transmission. We examined the cellular and subcellular distribution of the mGluR subtype 4a in spinal tissue by means of a specific antiserum and immunocytochemical techniques for light and electron microscopy. A dense plexus of mGluR4a‐immunoreactive elements was seen in the dorsal horn, with an apparent accumulation in lamina II. The immunostaining was composed of sparse immunoreactive fibres and punctate elements. No perikaryal staining was seen. Immunostaining for mGluR4a was detected in small to medium‐sized cells but not in large cells in dorsal root ganglia. At the electron microscopic level, superficial dorsal horn laminae demonstrated numerous immunoreactive vesicle‐containing profiles. Labelling was present in the cytoplasmic matrix, but accretion of immunoreaction product to presynaptic specialisations was commonly observed. Axolemmal labelling was confirmed by using a preembedding immunogold technique, which revealed distinctive deposits of gold immunoparticles along presynaptic thickenings with an average centre‐to‐centre distance of 41 nm (41.145 ± 13.59). Immunoreactive terminals often formed synaptic contacts with dendritic profiles immunonegative for mGluR4a. Immunonegative dendritic profiles were observed in apposition to both mGluR4a‐immunoreactive and immunonegative terminals. Diffuse immunoperoxidase reaction product was also detected in dendritic profiles, some of which were contacted by mGluR4a‐immunoreactive endings, but only occassionally were they observed to accumulate immunoreaction product along the postsynaptic density. Terminals immunoreactive for mGluR4a also formed axosomatic contacts. The present results reveal that mGluR4a subserves a complex spinal circuitry to which the primary afferent system seems to be a major contributor. J. Comp. Neurol. 430:448–457, 2001. © 2001 Wiley‐Liss, Inc.

[1]  J. Mateos,et al.  The metabotropic glutamate receptor subtype mGluR 2/3 is located at extrasynaptic loci in rat spinal dorsal horn synapses , 2000, Neuroscience Letters.

[2]  F. Conquet,et al.  Immunolocalization of the mGluR1b Splice Variant of the Metabotropic Glutamate Receptor 1 at Parallel Fiber‐Purkinje Cell Synapses in the Rat Cerebellar Cortex , 2000, Journal of neurochemistry.

[3]  T. Knöpfel,et al.  Immunocytochemical localization of the metabotropic glutamate receptor mGluR4a in the piriform cortex of the rat , 2000, The Journal of comparative neurology.

[4]  J. Bockaert,et al.  Complex interactions between mGluRs, intracellular Ca2+ stores and ion channels in neurons , 2000, Trends in Neurosciences.

[5]  T. Knöpfel,et al.  Clustering of the group III metabotropic glutamate receptor 4a at parallel fiber synaptic terminals in the rat cerebellar molecular layer , 1999, Neuroscience Research.

[6]  T. Knöpfel,et al.  Developmental expression of the group III metabotropic glutamate receptor mGluR4a in the medial nucleus of the trapezoid body of the rat , 1999, The Journal of comparative neurology.

[7]  W. Willis,et al.  Role of metabotropic glutamate receptor subtype mGluR1 in brief nociception and central sensitization of primate STT cells. , 1999, Journal of neurophysiology.

[8]  D. Hampson,et al.  Contribution of Metabotropic Glutamate Receptor mGluR4 to L‐2‐[3H]Amino‐4‐Phosphonobutyrate Binding in Mouse Brain , 1999, Journal of neurochemistry.

[9]  B Sakmann,et al.  Calcium Channel Types with Distinct Presynaptic Localization Couple Differentially to Transmitter Release in Single Calyx-Type Synapses , 1999, The Journal of Neuroscience.

[10]  W. Zieglgänsberger,et al.  Distribution and developmental changes in metabotropic glutamate receptor messenger RNA expression in the rat lumbar spinal cord. , 1999, Brain research. Developmental brain research.

[11]  R. A. Davidoff,et al.  Mechanisms involved in the metabotropic glutamate receptor‐enhancement of NMDA‐mediated motoneurone responses in frog spinal cord , 1999, British journal of pharmacology.

[12]  D. Budai,et al.  The involvement of metabotropic glutamate receptors in sensory transmission in dorsal horn of the rat spinal cord , 1998, Neuroscience.

[13]  M. J. Johnson,et al.  Antisense Ablation of Type I Metabotropic Glutamate Receptor mGluR1 Inhibits Spinal Nociceptive Transmission , 1998, The Journal of Neuroscience.

[14]  C. Cahill,et al.  Intrathecal administration of the mGluR compound, (S)-4CPG, attenuates hyperalgesia and allodynia associated with sciatic nerve constriction injury in rats , 1998, Pain.

[15]  T. Coderre,et al.  Hyperalgesia and allodynia induced by intrathecal (RS)‐dihydroxyphenylglycine in rats , 1998, Neuroreport.

[16]  B Sakmann,et al.  R-type Ca2+ currents evoke transmitter release at a rat central synapse. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  T. Coderre,et al.  In vivo antinociceptive activity of anti‐rat mGluR1 and mGluR5 antibodies in rats , 1998, Neuroreport.

[18]  T. Knöpfel,et al.  Localization of the mGlu4a metabotropic glutamate receptor in rat cerebellar cortex , 1998, Histochemistry and Cell Biology.

[19]  D. Laurie,et al.  Enhanced expression of metabotropic glutamate receptor 3 messenger RNA in the rat spinal cord during ultraviolet irradiation induced peripheral inflammation , 1997, Neuroscience.

[20]  P. Somogyi,et al.  Differential plasma membrane distribution of metabotropic glutamate receptors mGluR1α, mGluR2 and mGluR5, relative to neurotransmitter release sites , 1997, Journal of Chemical Neuroanatomy.

[21]  J. Sánchez-Prieto,et al.  Presynaptic Modulation of Glutamate Release Targets Different Calcium Channels in Rat Cerebrocortical Nerve Terminals , 1997, The European journal of neuroscience.

[22]  S. Wakisaka,et al.  Regeneration of periodontal primary afferents of the rat incisor following injury of the inferior alveolar nerve with special reference to neuropeptide Y-like immunoreactive primary afferents , 1997, Brain Research.

[23]  R. Shigemoto,et al.  Localization of a metabotropic glutamate receptor, mGluR7, in axon terminals of presumed nociceptive, primary afferent fibers in the superficial layers of the spinal dorsal horn: an electron microscope study in the rat , 1997, Neuroscience Letters.

[24]  T. Knöpfel,et al.  A Novel Splice Variant of a Metabotropic Glutamate Receptor, Human mGluR7b , 1997, Neuropharmacology.

[25]  P. O'Hara,et al.  Cloning and Characterization of a Metabotropic Glutamate Receptor, mGluR4b , 1997, Neuropharmacology.

[26]  T. Coderre,et al.  The contribution of metabotropic glutamate receptors (mGluRs) to formalin-induced nociception , 1996, Pain.

[27]  C. Romano,et al.  Metabotropic Glutamate Receptor 5 Is a Disulfide-linked Dimer* , 1996, The Journal of Biological Chemistry.

[28]  T. Coderre,et al.  Comparison of nociceptive effects produced by intrathecal administration of mGluR agonists. , 1996, Neuroreport.

[29]  J. Roder,et al.  Impaired Cerebellar Synaptic Plasticity and Motor Performance in Mice Lacking the mGluR4 Subtype of Metabotropic Glutamate Receptor , 1996, The Journal of Neuroscience.

[30]  I. Blümcke,et al.  Immunohistochemical distribution of metabotropic glutamate receptor subtypes mGluR1b, mGluR2/3, mGluR4a and mGluR5 in human hippocampus , 1996, Brain Research.

[31]  H. Wässle,et al.  Group II and Group III Metabotropic Glutamate Receptors in the Rat Retina: Distributions and Developmental Expression Patterns , 1996, The European journal of neuroscience.

[32]  P. Conn,et al.  Immunocytochemical localization of group III metabotropic glutamate receptors in the hippocampus with subtype-specific antibodies , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[33]  S. Nakanishi,et al.  Presynaptic localization of a metabotropic glutamate receptor, mGluR7, in the primary afferent neurons: an immunohistochemical study in the rat , 1995, Neuroscience Letters.

[34]  S. Nakanishi,et al.  Distributions of the mRNAs for L‐2‐amino‐4‐phosphonobutyrate‐sensitive metabotropic glutamate receptors, mGluR4 and mGluR7, in the rat brain , 1995, The Journal of comparative neurology.

[35]  S. Fleetwood-Walker,et al.  The involvement of metabotropic glutamate receptors and their intracellular signalling pathways in sustained nociceptive transmission in rat dorsal horn neurons , 1995, Neuropharmacology.

[36]  H. Shinozaki,et al.  Novel agonists for metabotropic glutamate receptors: trans- and cis-2-(2-carboxy-3-methoxymethylcyclopropyl)glycine (trans- and cis-MCG-I) , 1995, Neuropharmacology.

[37]  D. Budd,et al.  Co-existence and interaction between facilitatory and inhibitory metabotropic glutamate receptors and the inhibitory adenosine A1 receptor in cerebrocortical nerve terminals , 1995, Neuropharmacology.

[38]  D. Sunter,et al.  New phenylglycine derivatives with potent and selective antagonist activity at presynaptic glutamate receptors in neonatal rat spinal cord , 1995, Neuropharmacology.

[39]  T. Knöpfel,et al.  Metabotropic glutamate receptors: novel targets for drug development. , 1995, Journal of medicinal chemistry.

[40]  R. Duvoisin,et al.  A novel metabotropic glutamate receptor expressed in the retina and olfactory bulb , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[41]  R. Duvoisin,et al.  The metabotropic glutamate receptors: Structure and functions , 1995, Neuropharmacology.

[42]  E. F. Stanley,et al.  Localization of individual calcium channels at the release face of a presynaptic nerve terminal , 1994, Neuron.

[43]  Shigetada Nakanishi,et al.  Metabotropic glutamate receptors: Synaptic transmission, modulation, and plasticity , 1994, Neuron.

[44]  P. Ince,et al.  [3H]d-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study , 1994, Brain Research.

[45]  H. Schaible,et al.  Requirement of Metabotropic Glutamate Receptors for the Generation of Inflammation‐evoked Hyperexcitability in Rat Spinal Cord Neurons , 1994, The European journal of neuroscience.

[46]  H. Tse,et al.  Actions of two new antagonists showing selectivity for different sub‐types of metabotropic glutamate receptor in the neonatal rat spinal cord , 1994, British journal of pharmacology.

[47]  G. Westbrook,et al.  Cloning and expression of a new member of the L-2-amino-4-phosphonobutyric acid-sensitive class of metabotropic glutamate receptors. , 1994, Molecular pharmacology.

[48]  D. Jane,et al.  Antagonism of presynaptically mediated depressant responses and cyclic AMP-coupled metabotropic glutamate receptors. , 1994, European journal of pharmacology.

[49]  S. Nakanishi,et al.  Molecular characterization of a new metabotropic glutamate receptor mGluR7 coupled to inhibitory cyclic AMP signal transduction. , 1994, The Journal of biological chemistry.

[50]  M. Masu,et al.  Signal transduction, pharmacological properties, and expression patterns of two rat metabotropic glutamate receptors, mGluR3 and mGluR4 , 1993, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[51]  P. Suzdak,et al.  L-2-amino-4-phosphonobutyrate (L-AP4) is an agonist at the type iv metabotropic glutamate receptor which is negatively coupled to adenylate cyclase , 1992 .

[52]  S. Nakanishi Molecular diversity of glutamate receptors and implications for brain function. , 1992, Science.

[53]  S. Nakanishi,et al.  Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. , 1992, The Journal of biological chemistry.

[54]  S. Nakanishi,et al.  Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluRl, in transfected CHO cells , 1992, Neuron.

[55]  S. Nakanishi,et al.  A family of metabotropic glutamate receptors , 1992, Neuron.

[56]  R. Malenka,et al.  Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neonatal rat hippocampus. , 1991, The Journal of physiology.

[57]  E. F. Stanley Single calcium channels on a cholinergic presynaptic nerve terminal , 1991, Neuron.

[58]  Terri L. Gilbert,et al.  Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. , 1991, Science.

[59]  W. Zieglgänsberger,et al.  Fine structure and synaptic architecture of HRP‐labelled primary afferent terminations in lamina IIi of the rat dorsal horn , 1991, The Journal of comparative neurology.

[60]  S. Nakanishi,et al.  Sequence and expression of a metabotropic glutamate receptor , 1991, Nature.

[61]  G. Grant,et al.  Cytoarchitectonic organization of the spinal cord in the rat: II. The cervical and upper thoracic cord , 1989, The Journal of comparative neurology.

[62]  R. Giuffrida,et al.  Glutamate and aspartate immunoreactivity in corticospinal neurons of rats , 1989, The Journal of comparative neurology.

[63]  M. DeAngelis,et al.  D‐Aspartate Uptake and Release in the Guinea Pig Spinal Cord After Partial Ablation of the Cerebral Cortex , 1988, Journal of neurochemistry.

[64]  G. Grant,et al.  The cytoarchitectonic organization of the spinal cord in the rat. I. The lower thoracic and lumbosacral cord , 1984, The Journal of comparative neurology.

[65]  A. Ribeiro-da-Silva,et al.  Two types of synaptic glomeruli and their distribution in laminae I–III of the rat spinal cord , 1982, The Journal of comparative neurology.

[66]  M. Cuénod,et al.  Selective retrograde transport of d-aspartate in spinal interneurons and cortical neurons of rats , 1982, Brain Research.

[67]  D. Menétrey,et al.  Location and properties of dorsal horn neurons at origin of spinoreticular tract in lumbar enlargement of the rat. , 1980, Journal of neurophysiology.

[68]  H. Ralston,et al.  The distribution of dorsal root axons in laminae I, II and III of the macaque spinal cord: a quantitative electron microscope study. , 1979, The Journal of comparative neurology.

[69]  Takaaki AbeS,et al.  Molecular Characterization of a Novel Metabotropic Glutamate Receptor mGluR 5 Coupled to Inositol Phosphate / Ca 2 + Signal Transduction , 2001 .

[70]  J. Pin,et al.  Pharmacology and functions of metabotropic glutamate receptors. , 1997, Annual review of pharmacology and toxicology.

[71]  S. Fleetwood-Walker,et al.  Behavioural and electrophysiological evidence supporting a role for group I metabotropic glutamate receptors in the mediation of nociceptive inputs to the rat spinal cord. , 1997, Brain research.

[72]  S. Nakanishi,et al.  Molecular diversity and functions of glutamate receptors. , 1994, Annual review of biophysics and biomolecular structure.