An ACC–VTA–ACC positive-feedback loop mediates the persistence of neuropathic pain and emotional consequences

The central mechanisms underlying pain chronicity remain elusive. Here, we identify a reciprocal neuronal circuit in mice between the anterior cingulate cortex (ACC) and the ventral tegmental area (VTA) that mediates mutual exacerbation between hyperalgesia and allodynia and their emotional consequences and, thereby, the chronicity of neuropathic pain. ACC glutamatergic neurons (ACC^Glu) projecting to the VTA indirectly inhibit dopaminergic neurons (VTA^DA) by activating local GABAergic interneurons (VTA^GABA), and this effect is reinforced after nerve injury. VTA^DA neurons in turn project to the ACC and synapse to the initial ACC^Glu neurons to convey feedback information from emotional changes. Thus, an ACC^Glu–VTA^GABA–VTA^DA–ACC^Glu positive-feedback loop mediates the progression to and maintenance of persistent pain and comorbid anxiodepressive-like behavior. Disruption of this feedback loop relieves hyperalgesia and anxiodepressive-like behavior in a mouse model of neuropathic pain, both acutely and in the long term.