title: Presynaptic kainate receptors regulate spinal sensory transmission.
abstract: Small diameter dorsal root ganglion (DRG) neurons, which include cells that transmit nociceptive information into the spinal cord, are known to express functional kainate receptors. It is well established that exposure to kainate will depolarize C-fiber afferents arising from these cells. Although the role of kainate receptors on sensory afferents is unknown, it has been hypothesized that presynaptic kainate receptors may regulate glutamate release in the spinal cord. Here we show that kainate, applied at low micromolar concentrations in the presence of the AMPA-selective antagonist (RS)-4-(4-aminophenyl)-1, 2-dihydro-1-methyl-2-propyl-carbamoyl-6,7-methylenedioxyphthalazine++ +, suppressed spontaneous NMDA receptor-mediated EPSCs in cultures of spinal dorsal horn neurons. In addition, kainate suppressed EPSCs in dorsal horn neurons evoked by stimulation of synaptically coupled DRG cells in DRG-dorsal horn neuron cocultures. Interestingly, although the glutamate receptor subunit 5-selective kainate receptor agonist (RS)-2-alpha-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid (ATPA) (2 micrometer) was able to suppress DRG-dorsal horn synaptic transmission to a similar extent as kainate (10 micrometer), it had no effect on excitatory transmission between dorsal horn neurons. Agonist applications revealed a striking difference between kainate receptors expressed by DRG and dorsal horn neurons. Whereas DRG cell kainate receptors were sensitive to both kainate and ATPA, most dorsal horn neurons responded only to kainate. Finally, in recordings from dorsal horn neurons in spinal slices, kainate and ATPA were able to suppress NMDA and AMPA receptor-mediated EPSCs evoked by dorsal root fiber stimulation. Together, these data suggest that kainate receptor agonists, acting at a presynaptic locus, can reduce glutamate release from primary afferent sensory synapses.
authors.affiliation: Washington University Pain Center, Department of Anesthesiology, St. Louis, Missouri 63110, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: Kerchner
authors.forename: T J
authors.initials: TJ
authors.lastname: Wilding
authors.forename: P
authors.initials: P
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Zhuo
authors.forename: J E
authors.initials: JE
authors.lastname: Huettner
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D018680:Cholinergic Antagonists / Q000494:pharmacology; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D058788:GABA-B Receptor Antagonists; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism; D007608:Kainic Acid / Q000378:metabolism / Q000494:pharmacology; D009292:Narcotic Antagonists; D009475:Neurons, Afferent / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D020671:Posterior Horn Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000378:metabolism*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors; D018092:Kainic Acid Receptors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*
chemical_list: D018680:Cholinergic Antagonists; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D058788:GABA-B Receptor Antagonists; D018698:Glutamic Acid; D007608:Kainic Acid; D009292:Narcotic Antagonists; D058915:Purinergic P1 Receptor Antagonists; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate