Institute for Biomedical Sciences of Pain and Institute for Functional Brain Disorders, Tangdu Hospital, Fourth Military Medical University, Xi'an 710038, China.
Brain Res. 2011 Mar 25;1382:57-69. doi: 10.1016/j.brainres.2011.01.076. Epub 2011 Jan 31.
It is known that chronic pain affects various higher brain functions including perception, emotion, cognition, and memory. However, few studies have been performed to examine pain-induced synaptic plastic changes in the hippocampal formation (HF), an important region subserving affective-motivational component of pain. Our previous study has revealed a strong impact of peripheral persistent nociception on synaptic connection, transmission and function in the HF of rats, in both temporal and spatial domains, by using a newly developed MED64 multichannel recording system. However, the underlying signaling mechanisms for this pain-related spatial and temporal plasticity are still less understood. As an initial investigation, the present study attempted to examine potential different roles of the mitogen-activated protein kinase (MAPK) members in mediating this plastic phenomenon. By virtue of the three well-known MAPK inhibitors targeting extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK), respectively, in combination with the well-established MED64 multisite recording system, we found that pharmacological inhibition of the ERK- and JNK-mediated signaling pathway, at the plateau phase of the long-term potentiation (LTP), significantly decreased pain-enhanced LTP maintenance whereas similar blockade of p38 MAPK pathway dramatically further increased the potentiation. Regarding the spatial magnification of pain, ERK and p38 MAPK seemed to play opposing roles, with the former positively involved and the latter negatively involved, without any detectable effect of the JNK signaling pathway. Together, these results suggest differential roles of the specific members of the MAPK family in mediating pain-associated spatial and temporal plasticity in the HF, which are in good agreement with previous observations. In addition, a possible mechanistic separation between spatial and temporal magnification of pain is also indicated in this study.
已知慢性疼痛会影响包括感知、情感、认知和记忆在内的各种高级大脑功能。然而，很少有研究检查过海马结构（HF）中与疼痛的情感-动机成分有关的突触可塑性变化，而 HF 是一个重要的区域。我们之前的研究使用新开发的 MED64 多通道记录系统，揭示了外周持续性伤害感受对大鼠 HF 中突触连接、传递和功能的强烈影响，无论是在时间还是空间方面。然而，这种与疼痛相关的时空可塑性的潜在信号机制仍知之甚少。作为初步研究，本研究试图研究丝裂原活化蛋白激酶（MAPK）成员在介导这种可塑性现象中的潜在不同作用。通过分别针对细胞外信号调节激酶（ERK）、p38 MAPK 和 c-Jun N-末端激酶（JNK）的三种著名的 MAPK 抑制剂，结合成熟的 MED64 多部位记录系统，我们发现，在长时程增强（LTP）的平台期，ERK 和 JNK 介导的信号通路的药理学抑制显著降低了疼痛增强的 LTP 维持，而 p38 MAPK 通路的类似阻断则显著进一步增强了增强作用。关于疼痛的空间放大，ERK 和 p38 MAPK 似乎发挥了相反的作用，前者积极参与，后者消极参与，JNK 信号通路没有任何可检测到的作用。总之，这些结果表明 MAPK 家族的特定成员在介导 HF 中与疼痛相关的时空可塑性方面发挥了不同的作用，这与之前的观察结果一致。此外，本研究还表明疼痛的空间和时间放大之间可能存在机制分离。
