Role of Prelimbic GABAergic Circuits in Sensory and Emotional Aspects of Neuropathic Pain

• Peripheral nerve injury reduces activity of prelimbic area layer V pyramidal cells
• This hypoactivity is mediated by GABAergic feed-forward inhibition
• Optogenetic manipulation of GABAergic interneurons alters sensory pain responses
• Optogenetic modulation of GABA neuron firing alters emotional response to pain

SummaryNoxious stimuli are detected by peripheral nociceptors and then transmitted to higher CNS centers, where they are perceived as an unpleasant sensation. The mechanisms that govern the emotional component associated with pain are still incompletely understood. Here, we used optogenetic approaches both in vitro and in vivo to address this issue. We found that peripheral nerve injury inhibits pyramidal cell firing in the prelimbic area of the prefrontal cortex as a result of feed-forward inhibition mediated by parvalbumin-expressing GABAergic interneurons. In addition, activation of inhibitory archaerhodopsin or excitatory channelrhodopsin-2 in these neurons decreased and increased pain responses, respectively, in freely moving mice and accordingly modulated conditioned place preference scores and place escape/avoidance behavior. Our findings thus demonstrate an important role of the prelimbic area in sensory and emotional aspects of pain and identify GABAergic circuits in this region as a potential target for pain therapeutics.

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