Increased mGluR5 in somatostatin-positive interneurons mediates deactivation of the mPFC in a mouse model of neuropathic pain.

Understanding the neurobiological alterations associated with neuropathic pain is crucial for treatment interventions, but the underlying mechanisms remain unclear. We focused on the medial prefrontal cortex (mPFC), which undergoes various processes of plasticity during the development of neuropathic pain. In particular, in the neuropathic pain state, the pyramidal neuron activity is decreased and metabotropic glutamate receptor 5 (mGluR5) activity is increased in the mPFC. Here we investigated whether mGluR5 inactivation restores neuropathic pain in mice and, if so, how this inactivation affects local circuits in the mPFC. First, we confirmed the analgesic effect of mGluR5 inactivation in the mPFC using a pharmacological approach. Then, via electrophysiological recordings, we showed that the spontaneous inhibitory postsynaptic current (sIPSC) frequency in pyramidal neurons increased during the neuropathic pain state and that this change was attenuated by applying a mGluR5 antagonist. Also, the application of a mGluR5 agonist increased the sIPSC to layer 5 pyramidal neurons in naive mice, consistent with the findings in neuropathic pain conditions. Furthermore, somatostatin (SST)-expressing interneurons in the neuropathic pain group were more depolarized than those in the sham group through mGluR5 activation. Optogenetic inactivation of SST interneurons reversed the increase in sIPSC frequency of pyramidal neurons in the neuropathic pain group. Conversely, mGluR5 overexpression in SST interneurons in the mPFC of naive mice resulted in mechanical allodynia, a representative symptom of neuropathic pain. These results demonstrate that increased mGluR5 activity in SST interneurons contributes to neuropathic pain and that cell-type-specific modulation can provide new avenues for treating neuropathic pain.