Activation of VIP interneurons in the prefrontal cortex ameliorates neuropathic pain aversiveness

While dysfunction of the medial prefrontal cortex (mPFC) has been implicated in chronic pain, the underlying neural circuits and the contribution of specific cellular populations remain unclear. Using in vivo Ca2+ imaging, we report that in both male and female mice, peripheral nerve injury-induced neuropathic pain causes a marked reduction of vasoactive intestinal polypeptide (VIP)-expressing interneuron activity in the prelimbic area of the mPFC, which contributes to decreased prefrontal cortical outputs. Moreover, prelimbic glutamatergic projec-tions to GABAergic interneurons in the anterior cingulate cortex (ACC) are diminished, leading to loss of cortical -cortical inhibition and increased pyramidal neuron activity in the ACC. Chemogenetic activation of prelimbic VIP interneurons restores neuronal responses in the mPFC-ACC pathway and attenuates pain-like behaviors in mice. Furthermore, restoration of prelimbic outputs to the ACC reverses nerve injury-induced ACC hyperacti-vation. These findings reveal mPFC circuit changes associated with neuropathic pain and highlight VIP inter -neurons as potential therapeutic targets for pain treatment.

Automated summary

The dysfunction of VIP-expressing interneurons in the mPFC is associated with chronic pain, which leads to decreased prefrontal cortical outputs and increased pyramidal neuron activity in the ACC. Activation of VIP interneurons can restore neuronal responses in the mPFC-ACC pathway and attenuate pain-like behaviors.