Neuropathic Pain Linked to Defective Dopaminergic Inhibition in Anterior Cingulate Cortex

Pyramidal neurons in the anterior cingulate cortex (ACC), a prefrontal region involved in processing the affective components of pain, display hyperexcitability in chronic neuropathic conditions and their silencing abolishes hyperalgesia in rodents. We show here that dopamine, through D1-like receptor signaling, inhibits layer 2/3 pyramidal neurons of mouse ACC. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control the firing activity of these pyramidal neurons. Through Gs-coupled D1-like receptors, dopamine induces the opening of HCN channels at physiological membrane potentials, driving a significant decrease in input resistance and excitability. Systemic L-DOPA rescues HCN channel activity, pyramidal excitability in ACC as well as sensory phenotype in neuropathic mice while microinjection of a selective D1-like agonist in ACC induces relief of ongoing pain in neuropathic animals. We conclude that decreased dopaminergic inhibition in ACC plays a critical role in an abnormal top-down modulation leading to neuropathic pain.