The sensory and affective dimensions of neuropathic pain engage distinct interneuron plasticity patterns and separate circuitries in the medial prefrontal cortex.

Deactivation of the medial prefrontal cortex, a key center for cognition and motivational actions, is a common feature of several chronic pain conditions. However, which precise circuits underlie deactivation and altered output in chronic pain in vivo is not adequately understood. Here, unbiased longitudinal multiphoton imaging of GABAergic interneuron activity in the rodent prelimbic cortex revealed sensitization in all classes of GABAergic interneurons and a phenotypic switch from unimodality to polymodality after nerve injury. Targeted circuit interrogation revealed that distinct interneuron classes subserve different functions in fostering neuropathic pain and uncovered novel functions for the thus far unstudied caudal geminal eminence-derived interneurons. Remarkably, the sensory and emotional components of neuropathic pain engaged separate prelimbic output circuits comprising distinct types of excitatory neurons and projections. These results explain how the medial prefrontal cortex guides motivated actions to avoid or overcome pain and how loss thereof upon prefrontal deactivation exacerbates neuropathic pain.