Liu Yong, Zhou Li-Jun, Wang Jun, Li Dai, Ren Wen-Jie, Peng Jiyun, Wei Xiao, Xu Ting, Xin Wen-Jun, Pang Rui-Ping, Li Yong-Yong, Qin Zhi-Hai, Murugan Madhuvika, Mattson Mark P, Wu Long-Jun, Liu Xian-Guo
Pain Research Center and Department of Physiology, Zhongshan School of Medicine of Sun Yat-sen University, Guangzhou 510080, China.
Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
J Neurosci. 2017 Jan 25;37(4):871-881. doi: 10.1523/JNEUROSCI.2235-16.2016.
Clinical studies show that chronic pain is accompanied by memory deficits and reduction in hippocampal volume. Experimental studies show that spared nerve injury (SNI) of the sciatic nerve induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn, but impairs LTP in the hippocampus. The opposite changes may contribute to neuropathic pain and memory deficits, respectively. However, the cellular and molecular mechanisms underlying the functional synaptic changes are unclear. Here, we show that the dendrite lengths and spine densities are reduced significantly in hippocampal CA1 pyramidal neurons, but increased in spinal neurokinin-1-positive neurons in mice after SNI, indicating that the excitatory synaptic connectivity is reduced in hippocampus but enhanced in spinal dorsal horn in this neuropathic pain model. Mechanistically, tumor necrosis factor-alpha (TNF-α) is upregulated in bilateral hippocampus and in ipsilateral spinal dorsal horn, whereas brain-derived neurotrophic factor (BDNF) is decreased in the hippocampus but increased in the ipsilateral spinal dorsal horn after SNI. Importantly, the SNI-induced opposite changes in synaptic connectivity and BDNF expression are prevented by genetic deletion of TNF receptor 1 in vivo and are mimicked by TNF-α in cultured slices. Furthermore, SNI activated microglia in both spinal dorsal horn and hippocampus; pharmacological inhibition or genetic ablation of microglia prevented the region-dependent synaptic changes, neuropathic pain, and memory deficits induced by SNI. The data suggest that neuropathic pain involves different structural synaptic alterations in spinal and hippocampal neurons that are mediated by overproduction of TNF-α and microglial activation and may underlie chronic pain and memory deficits.
Chronic pain is often accompanied by memory deficits. Previous studies have shown that peripheral nerve injury produces both neuropathic pain and memory deficits and induces long-term potentiation (LTP) at C-fiber synapses in spinal dorsal horn (SDH) but inhibits LTP in hippocampus. The opposite changes in synaptic plasticity may contribute to chronic pain and memory deficits, respectively. However, the structural and molecular bases of these alterations of synaptic plasticity are unclear. Here, we show that the complexity of excitatory synaptic connectivity and brain-derived neurotrophic factor (BDNF) expression are enhanced in SDH but reduced in the hippocampus in neuropathic pain and the opposite changes depend on tumor necrosis factor-alpha/tumor necrosis factor receptor 1 signaling and microglial activation. The region-dependent synaptic alterations may underlie chronic neuropathic pain and memory deficits induced by peripheral nerve injury.
临床研究表明，慢性疼痛伴有记忆缺陷和海马体积减小。实验研究表明，坐骨神经的保留神经损伤（SNI）可诱导脊髓背角C纤维突触处的长时程增强（LTP），但会损害海马中的LTP。相反的变化可能分别导致神经性疼痛和记忆缺陷。然而，功能性突触变化背后的细胞和分子机制尚不清楚。在这里，我们表明，SNI后小鼠海马CA1锥体神经元的树突长度和棘密度显著降低，但脊髓神经激肽-1阳性神经元的树突长度和棘密度增加，这表明在这种神经性疼痛模型中，海马中的兴奋性突触连接减少，但脊髓背角中的兴奋性突触连接增强。机制上，肿瘤坏死因子-α（TNF-α）在双侧海马和同侧脊髓背角中上调，而脑源性神经营养因子（BDNF）在海马中减少，但在SNI后同侧脊髓背角中增加。重要的是，体内TNF受体1的基因缺失可防止SNI诱导的突触连接和BDNF表达的相反变化，并且在培养切片中TNF-α可模拟这种变化。此外，SNI激活了脊髓背角和海马中的小胶质细胞；小胶质细胞的药理学抑制或基因消融可防止SNI诱导的区域依赖性突触变化、神经性疼痛和记忆缺陷。数据表明，神经性疼痛涉及脊髓和海马神经元中不同的结构性突触改变，这些改变由TNF-α的过度产生和小胶质细胞激活介导，可能是慢性疼痛和记忆缺陷的基础。
慢性疼痛常伴有记忆缺陷。先前的研究表明，外周神经损伤会产生神经性疼痛和记忆缺陷，并在脊髓背角（SDH）的C纤维突触处诱导长时程增强（LTP），但会抑制海马中的LTP。突触可塑性的相反变化可能分别导致慢性疼痛和记忆缺陷。然而，这些突触可塑性改变的结构和分子基础尚不清楚。在这里，我们表明，在神经性疼痛中，SDH中兴奋性突触连接的复杂性和脑源性神经营养因子（BDNF）的表达增强，但海马中则降低，并且相反的变化取决于肿瘤坏死因子-α/肿瘤坏死因子受体1信号传导和小胶质细胞激活。区域依赖性突触改变可能是外周神经损伤诱导的慢性神经性疼痛和记忆缺陷的基础。
