Cichon Joseph, Blanck Thomas J J, Gan Wen-Biao, Yang Guang
Skirball Institute of Biomolecular Medicine, Department of Neuroscience and Physiology, New York University School of Medicine, New York, New York, USA.
Neuroscience Institute, New York University School of Medicine, New York, New York, USA.
Nat Neurosci. 2017 Aug;20(8):1122-1132. doi: 10.1038/nn.4595. Epub 2017 Jun 26.
Neuropathic pain involves long-lasting modifications of pain pathways that result in abnormal cortical activity. How cortical circuits are altered and contribute to the intense sensation associated with allodynia is unclear. Here we report a persistent elevation of layer V pyramidal neuron activity in the somatosensory cortex of a mouse model of neuropathic pain. This enhanced pyramidal neuron activity was caused in part by increases of synaptic activity and NMDA-receptor-dependent calcium spikes in apical tuft dendrites. Furthermore, local inhibitory interneuron networks shifted their activity in favor of pyramidal neuron hyperactivity: somatostatin-expressing and parvalbumin-expressing inhibitory neurons reduced their activity, whereas vasoactive intestinal polypeptide-expressing interneurons increased their activity. Pharmacogenetic activation of somatostatin-expressing cells reduced pyramidal neuron hyperactivity and reversed mechanical allodynia. These findings reveal cortical circuit changes that arise during the development of neuropathic pain and identify the activation of specific cortical interneurons as therapeutic targets for chronic pain treatment.
神经性疼痛涉及疼痛通路的长期改变，这会导致异常的皮层活动。目前尚不清楚皮层回路是如何改变并导致与异常性疼痛相关的强烈感觉的。在此，我们报告了在神经性疼痛小鼠模型的体感皮层中，V层锥体神经元活动持续升高。这种增强的锥体神经元活动部分是由顶树突棘突中的突触活动增加和NMDA受体依赖性钙尖峰引起的。此外，局部抑制性中间神经元网络改变了它们的活动，以利于锥体神经元的过度活跃：表达生长抑素和小白蛋白的抑制性神经元活动减少，而表达血管活性肠肽的中间神经元活动增加。对表达生长抑素的细胞进行药物遗传学激活可降低锥体神经元的过度活跃，并逆转机械性异常性疼痛。这些发现揭示了神经性疼痛发展过程中出现的皮层回路变化，并确定了特定皮层中间神经元的激活作为慢性疼痛治疗的靶点。
