JPET #173112 1 Functional Plasticity of Group II Metabotropic Glutamate Receptors in Regulating Spinal Excitatory and Inhibitory Synaptic Input in Neuropathic Pain

Metabotropic glutamate receptors (mGluRs) are involved in modulation of synaptic transmission and plasticity. Group II mGluRs in the spinal cord regulate glutamatergic input, but their functional changes in neuropathic pain are not clear. In this study, we determined the plasticity of spinal group II mGluRs in controlling excitatory and inhibitory synaptic transmission and nociception in neuropathic pain. Neuropathic pain was induced by spinal nerve ligation in rats, and whole-cell voltage-clamp recordings of glutamatergic excitatory postsynaptic currents (EPSCs) and spontaneous and miniature GABAergic and glycinergic inhibitory postsynaptic currents (sIPSCs and mIPSCs, respectively) were obtained in spinal cord slices. The specific group II mGluR agonist DCG-IV had a similar inhibitory effect on monosynaptic EPSCs evoked from the dorsal root in sham and nerve-injured rats. However, DCG-IV produced a greater inhibitory effect on evoked polysynaptic EPSCs and the frequency of sEPSCs in nerve-injured rats than in control rats. Although DCG-IV similarly reduced the frequency of GABAergic sIPSCs and mIPSCs in both groups, it distinctly inhibited the frequency of glycinergic sIPSCs and mIPSCs only in nerve-injured rats. The DCG-IV effect was blocked by the group II mGluR antagonist but not by the NMDA receptor antagonist. Strikingly, intrathecal injection of DCG-IV dose-dependently attenuated allodynia and hyperalgesia in nerve-injured rats but produced hyperalgesia in control rats. Our study provides new information that nerve injury upregulates group II mGluRs present on glutamatergic and glycinergic interneurons in the spinal cord. Activation of group II mGluRs reduces neuropathic pain probably by attenuating glutamatergic and glycinergic input to spinal dorsal horn neurons. This article has not been copyedited and formatted. The final version may differ from this version. JPET Fast Forward. Published on October 5, 2010 as DOI: 10.1124/jpet.110.173112 at A PE T Jornals on N ovem er 3, 2017 jpet.asjournals.org D ow nladed from