Chronic Monoarthritis Pain Accelerates the Processes of Cognitive Impairment and Increases the NMDAR Subunits NR2B in CA3 of Hippocampus from 5-month-old Transgenic APP/PS1 Mice.

Wei-Yi Gong,Hong-Yan Li,Zhi-Wei Zhao,Yuan Liu,Xu Zhang,He Jin,Jia-Xiang Ni,Rong Wang,Yu-Lan Wang

doi:10.3389/fnagi.2017.00123

Abstract

Many factors impact cognitive impairment; however, the effects of chronic pain and the mechanisms underlying these effects on cognitive impairment are currently unknown. Here we tested the hypothesis that chronic pain accelerates the transition from normal cognition to mild cognitive impairment (MCI) in 5-month-old transgenic APP/PS1 mice, an animal model of Alzheimer’s disease (AD), and that neurotoxicity induced by N-methyl-D-aspartic acid receptor (NMDAR) subunits may be involved in this process. Chronic monoarthritis pain was induced in transgenic APP/PS1 mice and 5-month-old wild-type (WT) mice by intra- and pre-articular injections of Freund’s complete adjuvant (FCA) into one knee joint. Pain behavior, learning and memory function, and the distribution and quantity of NMDAR subunits (NR1, NR2A and NR2B) in hippocampal CA1 and CA3 regions were assessed. Our results showed that although persistent and robust monoarthritis pain was induced by the FCA injections, only the transgenic APP/PS1 mice with chronic monoarthritis pain exhibited marked learning and memory impairments. This result suggested that chronic monoarthritis pain accelerated the cognitive impairment process. Furthermore, only transgenic APP/PS1 mice with chronic monoarthritis pain exhibited an overexpression of NR2B and an increased NR2B/NR2A ratio in the hippocampus CA3. These findings suggest that chronic pain is a risk factor for cognitive impairment and that increased neurotoxicity associated with NMDAR subunit activation may underpin the impairment. Thus, NMDARs may be a therapeutic target for the prevention of chronic pain-induced cognitive impairment.

Highlights

Mild cognitive impairment (MCI) is dysfunction in memory, learning and attention that is not dementia but is not normal for the given age and does not amount to significant impairments in functional activities (Petersen, 2004)
Because localization and subunit composition of N-methyl-D-aspartic acid receptor (NMDAR) appear to produce paradoxical actions and because NR1, NR2A and NR2B appear to be important for nociception and Alzheimer’s disease (AD), we investigated the distribution and expression of these subunits in the hippocampus
We found that NR2B protein expression was significantly increased in hippocampal CA3 tissue obtained from APP/PS1 transgenic animals with chronic monoarthritis pain

Summary

Introduction

Mild cognitive impairment (MCI) is dysfunction in memory, learning and attention that is not dementia but is not normal for the given age and does not amount to significant impairments in functional activities (Petersen, 2004). Several previous preclinical studies using inflammatory pain and neuropathic pain models have investigated the effects of pain on cognition, and their results confirm that pain worsens attention (Boyette-Davis et al, 2008; Pais-Vieira et al, 2009), emotional decision-making (Ji et al, 2010) and spatial learning and memory (Leite-Almeida et al, 2009; Hu et al, 2010). It is still unclear whether chronic pain alters the processes involved in the progression from normal cognition to dementia.

Objectives

Methods

Results

Discussion

Conclusion