Prof. Yu-Qiu Zhang and Prof. Ben-Long Liu published a paper in Neuron.

The mesocorticolimbic dopamine (DA) circuitry is implicated in chronic pain and comorbid depression, yet the specific receptor and circuit mechanisms distinguishing them remain unclear. Here, we show that orbitofrontal cortex (OFC) D1R- and D2R-expressing neurons serve as a checkpoint, independently mediating anxiodepression and allodynia in a trigeminal neuralgia (TN) mouse model. TN induced a hypodopaminergic state in the ventral tegmental area (VTA)-OFC circuit. Activation of the VTADA-OFC pathway effectively ameliorated TN-induced allodynia and anxiodepressive-like behaviors; these therapeutic effects were abolished by selective blockade of D2Rs and D1Rs, respectively. Activation of OFCD1 excitatory pyramidal neurons and their projections to the laterodorsal tegmental nucleus (LDTg) improved TN-induced anxiodepressive-like behaviors, whereas disinhibition or activation of OFC D2+ excitatory pyramidal neurons and their projections to the basolateral amygdaloid nucleus (BLA) produced analgesia. Thus, selectively targeting VTA-OFCD1 and VTA-OFCD2 or OFC D1Rs and D2Rs may provide new strategies for controlling different symptoms of chronic pain.

Link: https://doi.org/10.1016/j.neuron.2026.05.012