Metabotropic glutamate receptor subtypes 1 and 5 are activators of extracellular signal-regulated kinase signaling required for inflammatory pain in mice

Metabotropic glutamate receptors are expressed abundantly in the spinal cor d and have been shown to play important roles in the modulation of nocicept ive transmission and plasticity. Most previous studies have focused on the group I metabotropic glutamate receptors (mGluR1 and mGluR5) and activation of phospholipase C signaling by these receptors in modulating nociception. Recently, it was shown that the extracellular signal-regulated kinases (ER Ks)/mitogen-activated protein kinases are activated in spinal cord dorsal h orn neurons in response to stimulation of nociceptors and that ERK signalin g is involved in nociceptive plasticity. In the present studies, we sought to test the hypothesis that group I mGluRs modulate nociceptive transmissio n or plasticity via modulation of ERK signaling in dorsal horn neurons. We show that activation of mGluR1 and mGluR5 leads to activation of ERK1 and E RK2 in the spinal cord. Furthermore, we find that inflammation-evoked ERK a ctivation, which is required for nociceptive plasticity, is downstream of m GluR1 and mGluR5. Finally, we show colocalization of group I mGluRs with ac tivated ERK in dorsal horn neurons. These results show that mGluR1 and mGlu R5 are activated in dorsal horn neurons in response to peripheral inflammat ion and that activation of these group I mGluRs leads to activation of ERK1 and ERK2, resulting in enhanced pain sensitivity.