title: Inflammatory pain may induce cognitive impairment through an interlukin-6-dependent and postsynaptic density-95-associated mechanism.
abstract: 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.
authors.affiliation: From the Department of Anaesthesia, Critical Care and Pain Medicine, Geriatric Anaesthesia Research Unit, Massachusetts General Hospital of Harvard Medical School, Charlestown, Massachusetts.
authors.forename: Longqiu
authors.initials: L
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Xin
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Dong
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jianren
authors.initials: J
authors.lastname: Mao
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
mesh_terms: D000818:Animals; D001522:Behavior, Animal; D002540:Cerebral Cortex / Q000378:metabolism*; D003071:Cognition; D003072:Cognition Disorders / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D003213:Conditioning, Psychological; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D005239:Fear; D005620:Freund's Adjuvant; D051528:Guanylate Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D015850:Interleukin-6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D008568:Memory; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010146:Pain / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000523:psychology; D017288:Pain Threshold; D015398:Signal Transduction; D013997:Time Factors
chemical_list: D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D015850:Interleukin-6; D008565:Membrane Proteins; C577686:interleukin-6, mouse; D005620:Freund's Adjuvant; D051528:Guanylate Kinases