(S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord

(S)-3,4-Dicarboxyphenylglycine (DCPG) has been tested on cloned human mGlul -8 receptors individually expressed in AV12-664 cells co-expressing a rat g lutamate/aspartate transporter and shown to be a potent and selective mGlu8 a receptor agonist (EC50 value 31+/-2 nM, n=3) with weaker effects on the o ther cloned mGlu receptors (EC50 or IC50 values >3.5 muM on mGlu1-7). Electrophysiological characterisation on the neonatal rat spinal cord prepa ration revealed that (S)-3,4-DCPG depressed the fast component of the dorsa l root-evoked ventral root potential (fDR-VRP) giving a biphasic concentrat ion-response curve showing EC50 values of 1.3+/-0.2 muM (n=17) and 391+/-81 muM (n=17) for the higher and lower affinity components, respectively. The receptor mediating the high-affinity component was antagonised by 200 muM (S)-alpha -methyl-2-amino-4-phosphonobutyrate (MAP4, K-D value 5.4+/-1.5 mu M (n=3)), a group III metabotropic glutamate (mGlu) receptor antagonist. Th e a-methyl substituted analogue of (S)-3,4-DCPG, (RS)-3,4-MDCPG (100 muM), antagonised the effects of (S)-3,4-DCPG (K-D value 5.0+/-0.4 muM. n=3) in a similar manner to MAP4. (S)-3,4-DCPG-induced depressions of the fDR-VRP in the low-affinity range of the concentration-response curve were potentiate d by 200 muM (S)-alpha -ethylglutamate (EGLU), a group II mGlu receptor ant agonist, and were relatively unaffected by MAP4 (200 muM). However, depress ions of the fDR-VRP mediated by the AMPA selective antagonist (R)-3,4-DCPG were not potentiated by EGLU, suggesting that the low-affinity component of the concentration-response curve for (S)-3,4-DCPG is not due to antagonism of postsynaptic AMPA receptors. It is suggested that the receptor responsi ble for mediating the high-affinity component is mGlu8. The receptor respon sible for mediating the low-affinity effect of (S)-3,4-DCPG has yet to be i dentified but it is unlikely to be one of the known mGlu receptors present on primary afferent terminals or an ionotropic glutamate receptor of the AM PA or NMDA subtype. (C) 2001 Elsevier Science Ltd. All rights reserved.