Activation of group I mGlu receptors contributes to facilitation of NMDA receptor membrane current in spinal dorsal horn neurons after hind paw inflammation in rats

Abstract

The interaction between the group I metabotropic glutamate (mGlu) receptors and N-methyl-D-aspartate (NMDA) receptors plays a critical role in spinal hyperexcitability and hyperalgesia. The cellular mechanisms underlying this interaction remain unknown. Utilizing an ex vivo spinal slice preparation from young adult rats, we investigated the group I mGlu receptor modulation of NMDA receptor-mediated current in superficial dorsal horn neurons by patch clamp recording after complete Freund's adjuvant (CFA)-induced hind paw inflammation. We show that NMDA receptor-mediated dorsal root stimulation-evoked EPSC (eEPSC) and NMDA-induced current was enhanced in the inflamed rats, compared to naïve rats and this effect was attenuated by AIDA (1 mM), a group I mGlu receptor antagonist. There were also increases in the frequency and amplitude of miniature excitatory postsynaptic currents in the presence of tetrodotoxin, suggesting enhanced presynaptic glutamate release probability and postsynaptic membrane responsiveness in inflamed rats. DHPG (10 μM), a selective group I mGlu receptor agonist, further facilitated NMDA receptor-mediated eEPSC and NMDA-induced current in inflamed rats. The DHPG-produced facilitation of NMDA-induced current was blocked by intracellular dialysis of GDP-beta-S (1 mM), a G protein antagonist, and BAPTA (15 mM), an intracellular calcium chelating agent; and by pretreatment with U73,122 (10 μM), a PLC inhibitor, or 2-APB (100 μM), an IP₃-receptor antagonist. These findings support the hypothesis that signal transduction coupling between group I mGlu receptors and NMDA receptors underlies the activation of NMDA receptors in spinal hyperexcitability and hyperalgesia.