Differential activation of protein kinases in the dorsal horn in vitro of normal and inflamed rats by group I metabotropic glutamate receptor subtypes

Group I metabotropic glutamate receptors (mGluRs) contribute to spinal sensitization and synaptic plasticity but the underlying mechanisms are unknown. Here, group I mGluR modulation of evoked monosynaptic excitatory postsynaptic currents (EPSCs) in substantia gelatinosa (SG) neurones in vitro was investigated in juvenile rats. In addition, the role of group I mGluRs in dorsal horn neuronal Fos expression was determined in tetrodotoxin (TTX)-treated in vitro spinal cords of naïve rats and those with Complete Freund's Adjuvant (CFA) peripheral inflammation. In the majority of SG neurones, (S)-3,5-Dihydroxyphenylglycine (DHPG) reduced EPSCs and this effect was inhibited by the mGluR5 antagonist 2-Methyl-6-(phenylethynyl)-pyridine (MPEP). Data for paired-pulse and spontaneous miniature excitatory postsynaptic currents (mEPSCs) suggest mGluR5 acts presynaptically to reduce transmitter release. DHPG-induced reduction of EPSC amplitude operated via PKC, but not ERK, signalling cascade. In the dorsal horn of naïve but not CFA rats, DHPG increased Fos expression and this was reduced by MPEP and both PKC and ERK inhibitors. In the CFA group, basal Fos expression was reduced by MPEP and the kinase inhibitors. These data infer a role for mGluR5 in acute modulation of nociceptive synaptic efficacy within the dorsal horn and postsynaptic activation of transcription factors such as Fos that are implicated in activity-dependent neuroplastic adaptation. These actions are achieved by differential activation of PKC- and ERK-dependent transduction pathways.