Yang Longqiu, Xin Xin, Zhang Jie, Zhang Lei, Dong Yuanlin, Zhang Yiying, Mao Jianren, Xie Zhongcong
From the Department of Anaesthesia, Critical Care and Pain Medicine, Geriatric Anaesthesia Research Unit, Massachusetts General Hospital of Harvard Medical School, Charlestown, Massachusetts.
Anesth Analg. 2014 Aug;119(2):471-480. doi: 10.1213/ANE.0000000000000279.
Pain might be associated with cognitive impairment in humans. However, the characterization of such effects in a preclinical model and the investigation of the underlying mechanisms remain largely to be determined. We therefore sought to establish a system to determine the effect of pain on cognitive function in mice.
Complete Freund's adjuvant (CFA) was injected in the hindpaw of 5- to 8-month-old wild-type and interleukin-6 knockout mice. Learning and memory function, and the levels of interleukin-6 and postsynaptic density (PSD)-95 in the cortex and hippocampus of mice were assessed.
We found that the CFA injection-induced pain in the mice at 3 and 7 days after injection and decreased the freezing time (30.1 [16.5] vs 56.8 [28.1] seconds, P =0.023) in the tone test, which assesses the hippocampus-independent learning and memory function, but not in a context test of Fear Conditioning System (15.8 [6.7] vs 18.6 [8.8] seconds, P =0.622), which assesses the hippocampus-dependent learning and memory function, at 3 days after injection. Consistently, the CFA injection increased interleukin-6 (248% [11.6] vs 100% [7.9], P < 0.0001) and decreased the PSD-95 (40% [10.0] vs 100% [20.3], P < 0.0001) level in the cortex, but not hippocampus (95% [8.6] vs 100% [9.3], P =0.634), in the mice. The CFA injection induced neither reduction in the cortex PSD-95 levels nor cognitive impairment in the interleukin-6 knockout mice.
These results suggest that pain induced by CFA injection might increase interleukin-6 levels and decrease PSD-95 levels in the cortex, but not hippocampus of mice, leading to hippocampus-independent cognitive impairment in mice. These findings call for further investigation to determine the role of pain in cognitive function.
疼痛可能与人类认知障碍有关。然而，在临床前模型中此类效应的特征以及潜在机制的研究在很大程度上仍有待确定。因此，我们试图建立一个系统来确定疼痛对小鼠认知功能的影响。
将完全弗氏佐剂（CFA）注射到5至8月龄野生型和白细胞介素-6基因敲除小鼠的后爪中。评估小鼠的学习和记忆功能，以及小鼠皮质和海马中白细胞介素-6和突触后致密蛋白-95（PSD-95）的水平。
我们发现，注射CFA后3天和7天，小鼠出现注射诱导的疼痛，且在评估海马非依赖性学习和记忆功能的音调试验中，冻结时间缩短（30.1 [16.5] 秒对56.8 [28.1] 秒，P = 0.023），但在注射后3天评估海马依赖性学习和记忆功能的恐惧条件反射系统的情境试验中未出现缩短（15.8 [6.7] 秒对18.6 [8.8] 秒，P = 0.622）。同样，注射CFA后，小鼠皮质中的白细胞介素-6水平升高（248% [11.6] 对100% [7.9]，P < 0.0001），PSD-95水平降低（40% [10.0] 对100% [20.3]，P < 0.0001），但海马中的水平未出现变化（95% [8.6] 对100% [9.3]，P = 0.634）。注射CFA在白细胞介素-6基因敲除小鼠中既未导致皮质PSD-95水平降低，也未导致认知障碍。
这些结果表明，注射CFA诱导的疼痛可能会增加小鼠皮质而非海马中的白细胞介素-6水平，并降低PSD-95水平，导致小鼠出现海马非依赖性认知障碍。这些发现需要进一步研究以确定疼痛在认知功能中的作用。
