title: Surgical incision-induced nociception causes cognitive impairment and reduction in synaptic NMDA receptor 2B in mice.
abstract: Postoperative cognitive dysfunction (POCD) is associated with impairments in daily functioning, and increased morbidity and mortality. However, the causes and neuropathogenesis of POCD remain largely unknown. Uncontrolled pain often occurs postoperatively. We therefore set out to determine the effects of surgical incision-induced nociception on the cognitive function and its underlying mechanisms in 3- and 9-month-old mice. The mice had surgical incision in the hindpaw and then were tested for nociceptive threshold, learning, and memory. Brain levels of NMDA receptor and cyclin-dependent kinase 5 (CDK5) were also assessed. We found that surgical incision-induced nociception in mice led to a decreased freezing time in the tone test (which assesses the hippocampus-independent learning and memory function), but not the context test, of Fear Conditioning System at 3 and 7 d, but not 30 d post incision in 9-month-old, but not 3-month-old mice. Consistently, the surgical incision selectively decreased synaptic NMDA receptor 2B levels in the medial prefrontal cortex, and increased levels of tumor necrosis factor-α and CDK5 in the cortex, but not hippocampus, of the mice. Finally, eutectic mixture of local anesthetics and CDK5 inhibitor, roscovitine, attenuated the surgical incision-induced reduction in the synaptic NMDA receptor 2B levels and learning impairment. These results suggested that surgical incision-induced nociception reduced the synaptic NMDA receptor 2B level in the medial prefrontal cortex of mice, which might lead to hippocampus-independent learning impairment, contributing to POCD. These findings call for further investigation to determine the role of surgical incision-induced nociception in POCD.
authors.affiliation: Geriatric Anesthesia Research Unit, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, 02129-2060, Department of Anesthesia, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China, Department of Anesthesia, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, P.R. China, and Massachusetts General Hospital Center for Translational Pain Research, Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts 02129-2060.
authors.forename: Xiaoqin
authors.initials: X
authors.lastname: Zhang
authors.forename: Xin
authors.initials: X
authors.lastname: Xin
authors.forename: Yuanlin
authors.initials: Y
authors.lastname: Dong
authors.forename: Yiying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Buwei
authors.initials: B
authors.lastname: Yu
authors.forename: Jianren
authors.initials: J
authors.lastname: Mao
authors.forename: Zhongcong
authors.initials: Z
authors.lastname: Xie
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D003214:Conditioning, Classical / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D005260:Female; D007858:Learning / Q000502:physiology; D008297:Male; D051379:Mice; D059225:Nociception / Q000502:physiology*; D010146:Pain / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D017288:Pain Threshold / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000378:metabolism*
chemical_list: C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D051360:Cyclin-Dependent Kinase 5; C495906:Cdk5 protein, mouse