Presynaptic NMDA Receptors Modulate Glutamate Release from Primary Sensory Neurons in Rat Spinal Cord Dorsal Horn

NMDA receptors have the potential to produce complex activity-dependent regulation of transmitter release when localized presynaptically. In the somatosensory system, NMDA receptors have been immunocytochemically detected on presynaptic terminals of primary afferents, and these have been proposed to drive release of substance P from central terminals of a subset of nociceptors in the spinal cord dorsal horn. Here we report that functional NMDA receptors are indeed present at or near the central terminals of primary afferent fibers. Furthermore, we show that activation of these presynaptic receptors results in an inhibition of glutamate release from the terminals. Some of these NMDA receptors may be expressed in the preterminal axon and regulate the extent to which action potentials invade the extensive central arborizations of primary sensory neurons.

• Publication year

  2004

• Venue

  Journal of Neuroscience

• Publication date

  2004-03-17

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1523/JNEUROSCI.4637-03.2004PMID 15028770PMCID PMC6729523
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Synaptic Plasticity in Spinal Lamina I Projection Neurons That Mediate Hyperalgesia

  2003cited by this paper
• Primary afferent terminals that express presynaptic NR1 in rats are mainly from myelinated, mechanosensitive fibers

  2003influential reference
• Localization and function of ATP and GABAA receptors expressed by nociceptors and other postnatal sensory neurons in rat

  2003cited by this paper
• Ultrastructural study of glutamate- and GABA-immunoreactive terminals contacting the primary afferent fibers in frog spinal cord. A double postembedding immunocytochemical study.

  2003cited by this paper
• Immunohistochemical localization of N-methyl-D-aspartate receptor subunits in the adult murine hippocampal formation: evidence for a unique role of the NR2D subunit.

  2002cited by this paper
• Kainate Receptor-Dependent Short-Term Plasticity of Presynaptic Ca2+ Influx at the Hippocampal Mossy Fiber Synapses

  2002cited by this paper
• Involvement of presynaptic N-methyl-D-aspartate receptors in cerebellar long-term depression.

  2002cited by this paper
• Functional expression of AMPA receptors on central terminals of rat dorsal root ganglion neurons and presynaptic inhibition of glutamate release.

  2002influential reference
• Two N‐methyl‐D‐aspartate receptors in rat dorsal root ganglia with different subunit composition and localization

  2002influential reference
• Presynaptic Kainate Receptor Mediation of Frequency Facilitation at Hippocampal Mossy Fiber Synapses

  2001cited by this paper
• Presynaptic Kainate Receptors Regulate Spinal Sensory Transmission

  2001cited by this paper
• Localization of N-methyl-D-aspartate NR2B subunits on primary sensory neurons that give rise to small-caliber sciatic nerve fibers in rats.

  2000influential reference
• Distinct synaptic and extrasynaptic NMDA receptors identified in dorsal horn neurones of the adult rat spinal cord

  2000cited by this paper
• Dorsal root potential produced by a TTX‐insensitive micro‐circuitry in the turtle spinal cord

  2000cited by this paper
• Presynaptic N-methyl-D-aspartate receptors at the parallel fiber-Purkinje cell synapse.

  2000cited by this paper
• NMDA Receptor-Mediated Control of Presynaptic Calcium and Neurotransmitter Release

  1999influential reference
• Presynaptic Effects of NMDA in Cerebellar Purkinje Cells and Interneurons

  1999influential reference
• Presynaptic inhibition and neural control

  1998cited by this paper
• Ultrastructural analysis of NMDA, AMPA, and kainate receptors on unmyelinated and myelinated axons in the periphery

  1998cited by this paper
• NMDA EPSCs at Glutamatergic Synapses in the Spinal Cord Dorsal Horn of the Postnatal Rat

  1998cited by this paper
• Neurokinin 1 Receptor Internalization in Spinal Cord Slices Induced by Dorsal Root Stimulation Is Mediated by NMDA Receptors

  1997influential reference
• NMDA-receptor regulation of substance P release from primary afferent nociceptors

  1997cited by this paper
• Tonic facilitation of glutamate release by presynaptic N-methyl-D-aspartate autoreceptors in the entorhinal cortex.

  1996cited by this paper
• Evidence for presynaptic N-methyl-D-aspartate autoreceptors in the spinal cord dorsal horn.

  1994influential reference
• Developmental and regional expression in the rat brain and functional properties of four NMDA receptors.

  1994cited by this paper
• A simulation of action potentials in synaptic boutons during presynaptic inhibition.

  1994cited by this paper
• AMPA, KA and NMDA receptors are expressed in the rat DRG neurones.

  1993cited by this paper
• Kinetic study and numerical reconstruction of A-type current in granule cells of rat cerebellar slices.

  1993cited by this paper
• Glutamate receptor channels in rat DRG neurons: activation by kainate and quisqualate and blockade of desensitization by Con A.

  1990cited by this paper
• Release-enhancing glycine-dependent presynaptic NMDA receptors exist on noradrenergic terminals of hippocampus.

  1990cited by this paper
• Electrophysiological properties of subpopulations of rat dorsal root ganglion neurons in vitro.

  1990cited by this paper
• Computer study of presynaptic inhibition controlling the spread of action potentials into axonal terminals.

  1990cited by this paper
• Glutamate and substance P coexist in primary afferent terminals in the superficial laminae of spinal cord.

  1988cited by this paper
• The effect of changing extracellular potassium concentration on synaptic transmission in isolated spinal cords.

  1988influential reference
• Glutamate induces a depolarization of adult rat dorsal root ganglion neurons that is mediated predominantly by NMDA receptors.

  1988cited by this paper
• The primary afferent depolarizing action of kainate in the rat

  1986influential reference
• Sensory Mechanisms of the Spinal Cord

  1979cited by this paper
• Dorsal root potentials and changes in extracellular potassium in the spinal cord of the frog.

  1979influential reference
• Charge Movement Associated with the Opening and Closing of the Activation Gates of the Na Channels

  1974cited by this paper
• Central inhibitory action attributable to presynaptic depolarization produced by muscle afferent volleys

  1961influential reference
• Presynaptic and postsynaptic inhibition of monosynaptic reflexes

  1957influential reference

• Targeting Excitatory Glutamate Receptors for Morphine Tolerance: A Narrative Review

  2025cites this paper
• A review of dorsal root ganglia and primary sensory neuron plasticity mediating inflammatory and chronic neuropathic pain

  2024cites this paper
• Metamodulation of presynaptic NMDA receptors: New perspectives for pharmacological interventions.

  2023cites this paper
• Presynaptic glutamate receptors in nociception.

  2023cites this paper
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  2023cites this paper
• Elucidating afferent-driven presynaptic inhibition of primary afferent input to spinal laminae I and X

  2023cites this paper
• Multifactorial pathways in burn injury-induced chronic pain: novel targets and their pharmacological modulation

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• Advances and Barriers in Understanding Presynaptic N-Methyl-D-Aspartate Receptors in Spinal Pain Processing

  2022cites this paper
• Multimodal neuroimaging of metabotropic glutamate 5 receptors and functional connectivity in alcohol use disorder.

  2022cites this paper
• Presynaptic NMDARs on spinal nociceptor terminals state-dependently modulate synaptic transmission and pain

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• NMDARs mediate peripheral and central sensitization contributing to chronic orofacial pain

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• Delayed Onset Muscle Soreness and Critical Neural Microdamage-Derived Neuroinflammation

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• Experimental Protocols and Analytical Procedures for Studying Synaptic Transmission in Rodent Spinal Cord Dorsal Horn

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• Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels

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• The structure of sensory afferent compartments in health and disease

  2021cites this paper
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• Primary afferent-driven presynaptic inhibition of C-fiber inputs to spinal lamina I neurons.

  2020cites this paper
• Nicotinic receptor modulation of primary afferent excitability with selective regulation of Aδ-mediated spinal actions.

  2020cites this paper
• Qualitative review on N‐methyl‐D‐aspartate receptor expression in rat spinal cord during the postnatal development: Implications for central sensitization and pain

  2020influential citation
• Activation of EphB receptors contributes to primary sensory neuron excitability by facilitating Ca2+ influx directly or through Src kinase-mediated NMDA receptor phosphorylation.

  2020cites this paper
• Presynaptic NMDA receptors control nociceptive transmission at the spinal cord level in neuropathic pain

  2019cites this paper
• A role for the P2Y1 receptor in nonsynaptic cross-depolarization in the rat dorsal root ganglia

  2019cites this paper
• Distinct Modes of Presynaptic Inhibition of Cutaneous Afferents and Their Functions in Behavior.

  2019cites this paper
• Quantum energy levels of glutamate modulate neural biophotonic signals

  2018cites this paper
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  2018cites this paper
• Etiology and Pharmacology of Neuropathic Pain

  2018cites this paper
• Mechanisms of &mgr;‐opioid receptor inhibition of NMDA receptor‐induced substance P release in the rat spinal cord

  2018cites this paper
• Activity-dependent axonal plasticity in sensory systems.

  2018cites this paper
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  2013cites this paper
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  2012cites this paper
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  2012cites this paper
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  2011cites this paper
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  2011cites this paper
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  2011influential citation
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  2011cites this paper
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  2011cites this paper
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  2011cites this paper
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  2010influential citation
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  2010cites this paper
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  2010cites this paper
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