Montréal Neurological Institute, Department of Neurology & Neurosurgery, Alan Edwards Centre for Research on Pain, McGill University, Montréal, QC H3A 2B4, Canada.
Department of Pharmacology, Arizona Health Sciences Center, University of Arizona, Tucson, AZ 85721, USA.
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 G-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.
扣带皮层前部（ACC）中的锥体神经元参与处理疼痛的情感成分，在慢性神经性疼痛情况下表现出过度兴奋，其沉默会消除痛觉过敏。我们表明，多巴胺通过 D1 受体（D1R）信号通过调制超极化激活环核苷酸门控（HCN）通道来抑制小鼠 ACC 的锥体神经元。多巴胺激活 G 蛋白偶联的 D1R 会在生理膜电位下打开 HCN 通道，导致输入电阻和兴奋性显著降低。慢性神经性疼痛小鼠中的系统 L-DOPA 可挽救 HCN 通道活性，使 ACC 中的锥体神经元兴奋性正常化，并阻断机械和热痛觉过敏。此外，在 ACC 中微注射选择性 D1R 激动剂可缓解持续性神经性疼痛的不适，而 ACC D1R 拮抗剂可阻断加巴喷丁和利多卡因引起的镇痛作用。我们得出的结论是，ACC 中的多巴胺能抑制通过 D1R 在生理条件下起镇痛作用，而在慢性疼痛中则降低。
