Decoding Chronic Pain-induced Depression: Is GABA the Missing Link?

Chronic pain often occurs alongside mood disorders, with studies showing they share common neural pathways. A key player in this comorbidity is the anterior cingulate cortex (ACC), a region responsible for processing the emotional, sensory, and cognitive aspects of pain and mood regulation. Notably, ACC dysfunction in comorbid pain and depression is characterized by an imbalance of excitation and inhibition, resulting in hyperexcitability. GABAergic neurons, in particular, seem central to these alterations. Data from our group has shown that optogenetic activation of ACC GABAergic neurons can successfully increase depressive-like behaviors in naïve mice and reduce depressive-like behaviors in rodents with comorbid pain and depression. Hence, we hypothesize that chronic pain-induced depression disrupts GABAergic neurons in the ACC, reducing their ability to inhibit neural circuits. This leads to hyperexcitability, which may drive anxiodepressive-like behaviors. In vivo fiber photometry recordings of mice with chronic pain-induced depression have shown we have altered GABAergic activity in tasks associated with anxiety and depressive-like behaviors, indicating a potential malfunction of the inhibitory network in ACC. In addition, sequencing data of GABAergic cells have also shown genetic alterations which may significantly contribute to the observed changes. Taken together, these findings highlight GABAergic functioning in the ACC as a key element in the pathophysiology of comorbid pain and depression.

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