Decreased dopaminergic inhibition of pyramidal neurons in anterior cingulate cortex maintains chronic neuropathic pain

Cell Rep. 2021 Nov 30;37(9):109933. doi: 10.1016/j.celrep.2021.109933.


Pyramidal neurons in the anterior cingulate cortex (ACC), a prefrontal region involved in processing the affective components of pain, display hyperexcitability in chronic neuropathic pain conditions, and their silencing abolishes hyperalgesia. We show that dopamine, through D1 receptor (D1R) signaling, inhibits pyramidal neurons of mouse ACC by modulation of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Activation of Gs-coupled D1R by dopamine induces the opening of HCN channels at physiological membrane potentials, driving a significant decrease in input resistance and excitability. Systemic L-DOPA in chronic neuropathic mice rescues HCN channel activity, normalizes pyramidal excitability in ACC, and blocks mechanical and thermal allodynia. Moreover, microinjection of a selective D1R agonist in the ACC relieves the aversiveness of ongoing neuropathic pain, while an ACC D1R antagonist blocks gabapentin- and lidocaine-evoked antinociception. We conclude that dopaminergic inhibition via D1R in ACC plays an analgesic role in physiological conditions and is decreased in chronic pain.

Keywords: D1 receptor; HCN channels; chronic pain; dopamine; levodopa; monoamines; neuromodulation; ongoing pain relief; pain aversiveness; prefrontal cortex; top-down pain modulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dopamine / metabolism*
  • Dopamine Agents / pharmacology
  • Gyrus Cinguli / drug effects*
  • Gyrus Cinguli / metabolism
  • Gyrus Cinguli / pathology
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / genetics
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / metabolism*
  • Levodopa / pharmacology*
  • Male
  • Membrane Potentials
  • Neuralgia / etiology
  • Neuralgia / metabolism
  • Neuralgia / pathology
  • Neuralgia / prevention & control*
  • Potassium Channels / genetics
  • Potassium Channels / metabolism*
  • Pyramidal Cells / drug effects*
  • Pyramidal Cells / metabolism
  • Pyramidal Cells / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Dopamine D1 / agonists*


  • Dopamine Agents
  • Hcn1 protein, rat
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • Potassium Channels
  • Receptors, Dopamine D1
  • Levodopa
  • Dopamine