Understanding the neurobiological alterations associated with neuropathic pain is crucial for treatment interventions, but the underlying mechanisms are not fully understood. Neuropathic pain causes many alterations in brain regions, including the medial prefrontal cortex (mPFC). The mPFC activity is decreased in the neuropathic pain state, which is associated with increased metabotropic glutamate receptor 5 (mGluR5) activity in this region. Here, we investigated whether mGluR5 inactivation restores neuropathic pain 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 frequency of sIPSCs in pyramidal neurons increases during neuropathic pain and that this change is attenuated by the application of a mGluR5 antagonist. Furthermore, the application of a mGluR5 agonist increased the spontaneous inhibitory postsynaptic current (sIPSC) to layer 5 pyramidal neurons in naïve mice, consistent with the findings in neuropathic pain conditions. Additionally, we found that the somatostatin interneurons in the mPFC in the neuropathic pain group were more depolarized than those in the sham group. Optogenetic inactivation of somatostatin interneuron canceled out the observed increase in inhibition of pyramidal neurons in the neuropathic pain state. Conversely, mGluR5 overexpression in the somatostatin interneuron in the mPFC of naive mice caused mechanical allodynia, a representative symptom of neuropathic pain. These results demonstrate that increased mGluR5 activity in somatostatin interneuron accounts for neuropathic pain and that cell type-specific modulation can provide new avenues for treating neuropathic pain.