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.