title: Modulation of primary afferent-mediated neurotransmission and Fos expression by glutamate uptake inhibition in rat spinal neurones in vitro.
abstract: The effect of altered endogenous levels of synaptic glutamate on neurotransmission and synaptic dorsal horn Fos expression was determined in rat spinal cord in vitro. The uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxylate (L-PDC, 1mM) was tested against dorsal root-ventral root potentials (DR-VRP), afferent-mediated slow dorsal horn excitatory postsynaptic potentials (DR-EPSP) and nociceptive afferent-induced synaptic currents (EPSCs) of substantia gelatinosa neurones. L-PDC reduced DR-VRP fast and slow peak amplitude and duration (P<0.05), slow DR-EPSP amplitude and duration (P<0.005) and EPSC amplitude (P<0.05). The Group II/III mGluR antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG, 100 microM) reduced L-PDC inhibition of synaptic potentials. The Group II antagonist (2S)-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495, 300 nM) and the Group III antagonist (RS)-alpha-methylserine-O-phosphate (MSOP, 10 microM) partially reversed EPSC inhibition by L-PDC. The Group III agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4, 30 microM) mimicked CPPG-sensitive inhibitory effects of L-PDC on DR-VRP (P<0.001) and the slow DR-EPSP (P<0.005). L-PDC (1mM) or L-AP4 (30 microM) reduced afferent-evoked dorsal horn Fos expression, this effect was reversed by CPPG. These data suggest that increased synaptic glutamate levels may activate inhibitory Group II/III mGluR receptors and impact significantly on nociceptive neurotransmission and transcriptional adaptive responses of target neurones.
authors.affiliation: School of Biomedical Sciences, University of Leeds, Leeds LS2 9NQ, UK.
authors.forename: G C
authors.initials: GC
authors.lastname: Bird
authors.forename: A U
authors.initials: AU
authors.lastname: Asghar
authors.forename: M A
authors.initials: MA
authors.lastname: Ackley
authors.forename: A E
authors.initials: AE
authors.lastname: King
mesh_terms: D000344:Afferent Pathways / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003998:Dicarboxylic Acids / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D016762:Genes, fos / Q000187:drug effects; D018698:Glutamic Acid / Q000096:biosynthesis*; D005998:Glycine / Q000031:analogs & derivatives* / Q000494:pharmacology; D066298:In Vitro Techniques; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism*; D011422:Propionates / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000096:biosynthesis* / Q000235:genetics; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats
chemical_list: C114785:2-amino-4-phosphono-propinate; D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; D014179:Neurotransmitter Uptake Inhibitors; D011422:Propionates; D016760:Proto-Oncogene Proteins c-fos; D011759:Pyrrolidines; C104331:cyclopropyl-4-phosphonophenylglycine; D018698:Glutamic Acid; C083486:pyrrolidine-2,4-dicarboxylic acid; D005998:Glycine