D1R-specific modulation of ACC mitigates chronic neuropathic pain

Abstract

Maladaptive plasticity within central pain circuits is a defining feature of chronic neuropathic pain, yet the mechanisms governing these changes remain unclear. This study investigates the role of the mesocortical dopaminergic pathway in the neuropathic pain-induced hyperexcitability of dopamine D1 receptor-expressing anterior cingulate cortex (ACCD1R) neurons. We find that infusing D1R agonists in the ACC reverses the mechanical hypersensitivity and negative affective-motivational affect in mice caused by spared-nerve injury (SNI). Although ACC pyramidal neurons are widely presumed to be the principal targets of D1R signaling, ex vivo recordings reveal that D1R agonists suppress the excitability of D1R-expressing pyramidal neurons while enhancing the excitability of D1R-expressing interneurons. Consistently, gene-expression analyses show that D1R-expression is distributed across both excitatory and inhibitory ACC neurons. Furthermore, we demonstrate that the excitability of genetically labeled D1R pyramidal neurons is enhanced by SNI, whereas in interneurons, it is reduced. Chemogenetic manipulation demonstrates that activation of D1R neurons produces robust analgesic and anxiolytic effects, whereas inhibition worsens pain- and anxiety-related behaviours, indicating that inhibitory D1R neurons dominate population-level output. Circuit tracing further delineates diverse afferent and efferent connections linking ACCD1R neurons to sensory and affective pain pathways. Together, these results identify dopaminergic regulation of ACCD1R neurons as a critical determinant of cortical dysfunction in chronic pain.