Inflammatory Pain May Induce Cognitive Impairment Through an Interlukin-6-Dependent and Postsynaptic Density-95-Associated Mechanism

Yang, Longqiu MD, PhD; Xin, Xin MD; Zhang, Jie MD; Zhang, Lei MD, PhD; Dong, Yuanlin MD; Zhang, Yiying MD; Mao, Jianren MD, PhD; Xie, Zhongcong MD, PhD

doi: 10.1213/ANE.0000000000000279
Pain and Analgesic Mechanisms: Research Report

BACKGROUND: 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.

METHODS: 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.

RESULTS: 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.

CONCLUSIONS: 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.

Published ahead of print May 30, 2014.

From the Department of Anaesthesia, Critical Care and Pain Medicine, Geriatric Anaesthesia Research Unit, Massachusetts General Hospital of Harvard Medical School, Charlestown, Massachusetts.

Longqiu Yang, MD, PhD, is currently affiliated with Department of Anesthesiology, The First People’s Hospital Changzhou and The Third Affiliated Hospital of Soochow University, Changzhou, China.

Xin Xin, MD, is currently affiliated with Department of Anaesthesia, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, P. R. China.

Jie Zhang, MD, is currently affiliated with Department of Anaesthesiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.

Lei Zhang, MD, PhD, is currently affiliated with Department of Anesthesiology, East Hospital, Tongji University School of Medicine, Shanghai, P. R. China. Research Center for Translational Medicine, East Hospital, Tongji University School of Medicine, Shanghai, P. R. China.

Accepted for publication January 29, 2014.

Published ahead of print May 30, 2014.

Funding: This research was supported by R21AG038994, R01 GM088801, and R01 AG041274 from National Institutes of Health, Bethesda, Maryland, Investigator-initiated Research grant from Alzheimer’s Association, Chicago, Illinois, and Cure Alzheimer’s Fund, Wellesley, Massachusetts to Zhongcong Xie.

The authors declare no conflicts of interest.

Drs. LongqiuYang and Xin Xin contributed equally to this manuscript.

Reprints will not be available from the authors.

Address correspondence to Zhongcong Xie, MD, PhD, Department of Anaesthesia, Critical Care and Pain Medicine, Geriatric Anaesthesia Research Unit, Massachusetts General Hospital and Harvard Medical School, 149 13th St., Room 4310, Charlestown, MA 02129-2060. Address e-mail to zxie@mgh.harvard.edu.

© 2014 International Anesthesia Research Society