Modulation of primary afferent-mediated neurotransmission and Fos expression by glutamate uptake inhibition in rat spinal neurones in vitro

The effect of altered endogenous levels of synaptic glutamate on neurotrans mission and synaptic dorsal horn Fos expression was determined in rat spina l cord in vitro. The uptake inhibitor L-trans-pyrrolidine-2,4-dicarboxy lat e (L-PDC, 1 mM) 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 su bstantia gelatinosa neurones. L-PDC reduced DR-VRP fast and slow peak ampli tude and duration (P<0.05), slow DR-EPSP amplitude and duration (P<0.005) a nd EPSC amplitude (P<0.05). The Group II/III mGluR antagonist (RS)-<alpha>- cyclopropyl-4-phosphonophenylglycine (CPPG, 100 muM) reduced L-PDC inhibiti on 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 muM ) partially reversed EPSC inhibition by L-PDC. The Group III agonist L(+)-2 -amino-4-phosphonobutyric acid (L-AP4, 30 muM) mimicked CPPG-sensitive inhi bitory effects Of L-PDC on DR-VPP (P<0.001) and the slow DR-EPSP (P<0.005). L-PDC (1 mM) or L-AP4 (30 muM) reduced afferent-evoked dorsal horn Fos exp ression, this effect was reversed by CPPG. These data suggest that increase d synaptic glutamate levels may activate inhibitory Group II/III mGluR rece ptors and impact significantly on nociceptive neurotransmission and transcr iptional adaptive responses of target neurones. (C) 2001 Elsevier Science L td.