Decreased dopaminergic inhibition of pyramidal neurons in anterior cingulate cortex maintains chronic neuropathic pain.
Decreased dopaminergic inhibition of pyramidal neurons in anterior cingulate cortex maintains chronic neuropathic pain.
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DOI：
10.1016/j.celrep.2021.109933
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发表时间：
2021-11-30
期刊：
影响因子：
8.8
通讯作者：
Séguéla P
中科院分区：
文献类型：
--
作者：
Lançon K;Qu C;Navratilova E;Porreca F;Séguéla P
前扣带皮层（ACC）中的锥体神经元（参与处理疼痛情感成分的前额叶区域）在慢性神经性疼痛条件下显示出过度兴奋性，并且它们的沉默消除了痛觉过敏。我们表明，多巴胺，通过D1受体（D1 R）信号，抑制小鼠ACC锥体神经元的超极化激活的环核苷酸门控（HCN）通道的调制。多巴胺激活Gs-coupled D1 R可诱导HCN通道在生理膜电位下开放，导致输入电阻和兴奋性显著降低。慢性神经病小鼠的全身性L-DOPA挽救HCN通道活性，使ACC中的锥体兴奋性正常化，并阻断机械和热异常性疼痛。此外，在ACC中微量注射选择性D1 R激动剂缓解了持续神经性疼痛的厌恶性，而ACC D1 R拮抗剂阻断了加巴喷丁和利多卡因诱发的抗伤害感受。我们的结论是，多巴胺能抑制通过D1 R在ACC发挥镇痛作用的生理条件下，在慢性疼痛减少。Lançon等人表明，多巴胺通过D1 R信号传导和随后的HCN通道开放抑制前扣带皮层（ACC）中的锥体神经元。ACC D1 R的激活提供镇痛，并且对于缓解持续疼痛是必要的。补充脊髓上多巴胺使ACC锥体兴奋性正常化并减少神经性痛觉过敏。
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. Lançon et al. show that dopamine inhibits pyramidal neurons in the anterior cingulate cortex (ACC) via D1R signaling and subsequent opening of HCN channels. Activation of ACC D1R provides analgesia and is necessary for relief of ongoing pain. Supplementing supraspinal dopamine normalizes ACC pyramidal hyperexcitability and reduces neuropathic hyperalgesia.
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影响因子：
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