Interaction of group I mGlu and NMDA receptor agonists within the dorsal horn of the spinal cord of the juvenile rat

Abstract

1 The modulatory eects of mGlu receptors on NMDA-induced potential changes in spinal motoneurones were studied in vitro. 2 Selective activation of mGlu5 receptors by 10 mM (RS)-2-Chloro-5-hydroxyphenylglycine (CHPG; EC 50 =280+24 mM) did not produce any change in the ventral root potential. However, the same concentration of CHPG (10 min perfusion) signi®cantly attenuated the NMDA-induced ventral root depolarization (VRD). The eect persisted for 10 min after washout. NMDA-induced responses returned to control in 30 min. Brief co-application of CHPG and NMDA did not alter the NMDA-induced response indicating lack of direct receptor interaction. 3 The attenuating eect of CHPG on the NMDA-induced VRD was inhibited by the mGluR5 receptor antagonist, 2-methyl-6-phenyl-ethynylpyridine (MPEP). 4 In the presence of CGP56433A, a GABA B receptor antagonist, the NMDA-induced VRD was unchanged. However, NMDA-induced responses were potentiated after 10 min co-application of CHPG and CGP56433A. 5 (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylate ((2R,4R)-APDC), a group II mGlu receptor agonist did not attenuate the NMDA-induced response. 6 Under normal physiological conditions group I mGlu receptor agonists activate at least two populations of neurones: (1) GABA-ergic cells, which could release GABA and inhibit dorsal horn neurones, and (2) deep dorsal horn neurones/motoneurones which express NMDA receptors. Therefore, activation of mGlu5 receptors located on GABA-ergic interneurones could in¯uence any direct potentiating interaction between mGlu5 and NMDA receptors in spinal cord and result in depression of the VRD. In the presence of a GABA B receptor antagonist, the direct synergistic interaction is unmasked. These data suggest that group I mGlu receptors provide a complex modulation of spinal synaptic processes.

Pharmacology of Basimglurant (RO4917523, RG7090), a Unique Metabotropic Glutamate Receptor 5 Negative Allosteric Modulator in Clinical Development for Depression

“…Glutamate is an important neurotransmitter in the context of nociception (Dickenson et al, 1997), and mGlu5 is expressed in the spinal cord and dorsal root ganglia (Shigemoto and Mizuno, 2000;Dang et al, 2002), where it has been implicated in neuropathic pain (Hu et al, 2012;Radulovic and Tronson, 2012). With this background, we studied basimglurant for its antinociceptive potential.…”

Distinct subtypes of group I metabotropic glutamate receptors on rat spinal neurons mediate complex facilitatory and inhibitory effects

“…Because DHPG can facilitate NMDA receptor activity (Holohean et al ., 1999; Ugolini et al ., 1999; Dang et al ., 2002), we tested whether DHPG‐induced oscillations were dependent on NMDA receptor activation (Fig. 5C).…”

“…For example, while DHPG is reported to increase NMDA and AMPA receptor‐mediated responses (Dong & Feldman, 1999; Ugolini et al ., 1999), this result is thought to be due to a generalized enhancement of cell excitability (Jones & Headley, 1995). Although mGlu5 receptor activity is reported to facilitate GABAergic transmission as well as NMDA receptor‐mediated responses, it is suggested that the overall action is an inhibitory one (Dang et al ., 2002).…”

Modulation of rhythmic patterns and cumulative depolarization by group I metabotropic glutamate receptors in the neonatal rat spinal cord in vitro

“…In the rat spinal cord group I mGluRs increase motoneuron excitability (Dong & Feldman, 1999; Ugolini et al. , 1999) together with facilitation of inhibitory transmission (Dang et al. , 2002).…”

“…The mammalian spinal cord mainly expresses group I mGluRs (Valerio et al, 1997;Berthele et al, 1999;Alvarez et al, 2000) which, via intracellular Ca 2 release and inositol-triphosphate formation, modulate Ca 2 and K conductances (Pin & Duvoisin, 1995;Anwyl, 1999;Schoepp et al, 1999;Fagni et al, 2000). In the rat spinal cord group I mGluRs increase motoneuron excitability (Dong & Feldman, 1999;Ugolini et al, 1999) together with facilitation of inhibitory transmission (Dang et al, 2002). Therefore, it seems important to understand how such effects may be translated into rhythmic patterns.…”