Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation
Dysfunction of Cortical Dendritic Integration in Neuropathic Pain Reversed by Serotoninergic Neuromodulation
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DOI：
10.1016/j.neuron.2015.03.003
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发表时间：
2015-04-08
期刊：
影响因子：
16.2
通讯作者：
Nevian, Thomas
中科院分区：
文献类型：
--
作者：
Santello, Mirko;Nevian, Thomas
神经性疼痛是由周围神经系统、脊髓和脊髓上区域的神经元功能的长期改变引起的。尽管前脑的功能变化被认为导致持续性疼痛的发生，但其重要性和精确的亚细胞性质仍有待探索。利用前扣带皮层神经元的体细胞和树突状全细胞膜片钳记录，我们发现坐骨神经损伤导致第5层锥体神经元树突中超极化激活的环核苷酸调节（HCN）通道的活动依赖性功能障碍，导致兴奋性突触后输入的整合增强和神经元放电增加。 7 型血清素受体 (5-HT7R) 的特异性激活通过增加 HCN 通道功能、恢复正常树突整合并减少体内神经损伤动物的机械性疼痛超敏反应来减轻病变诱发的病理。因此，前脑水平的血清素能神经调节可以逆转神经性疼痛引起的树突功能障碍，并可能代表潜在的治疗靶点。
Neuropathic pain is caused by long-term modifications of neuronal function in the peripheral nervous system, the spinal cord, and supraspinal areas. Although functional changes in the forebrain are thought to contribute to the development of persistent pain, their significance and precise subcellular nature remain unexplored. Using somatic and dendritic whole-cell patch-clamp recordings from neurons in the anterior cingulate cortex, we discovered that sciatic nerve injury caused an activity-dependent dysfunction of hyperpolarization-activated cyclic nucleotide-regulated (HCN) channels in the dendrites of layer 5 pyramidal neurons resulting in enhanced integration of excitatory postsynaptic inputs and increased neuronal firing. Specific activation of the serotonin receptor type 7 (5-HT7R) alleviated the lesion-induced pathology by increasing HCN channel function, restoring normal dendritic integration, and reducing mechanical pain hypersensitivity in nerve-injured animals in vivo. Thus, serotoninergic neuromodulation at the forebrain level can reverse the dendritic dysfunction induced by neuropathic pain and may represent a potential therapeutical target.