Brain Microglial Activation in Chronic Pain-Associated Affective Disorder.

Ellane Eda Barcelon,Woo-Hyun Cho,Sung Joong Lee,Sang Beom Jun

doi:10.3389/fnins.2019.00213

Ellane Eda Barcelon, Woo-Hyun Cho + Show 2 more

Open Access

https://doi.org/10.3389/fnins.2019.00213

Copy DOI

Abstract

A growing body of evidence from both clinical and animal studies indicates that chronic neuropathic pain is associated with comorbid affective disorders. Spinal cord microglial activation is involved in nerve injury-induced pain hypersensitivity characterizing neuropathic pain. However, there is a lack of thorough assessments of microglial activation in the brain after nerve injury. In the present study, we characterized microglial activation in brain sub-regions of CX3CR1GFP/+ mice after chronic constriction injury (CCI) of the sciatic nerve, including observations at delayed time points when affective brain dysfunctions such as depressive-like behaviors typically develop. Mice manifested chronic mechanical hypersensitivity immediately after CCI and developed depressive-like behaviors 8 weeks post-injury. Concurrently, significant increases of soma size and microglial cell number were observed in the medial prefrontal cortex (mPFC), hippocampus, and amygdala 8 weeks post-injury. Transcripts of CD11b, and TNF-α, genes associated with microglial activation or depressive-like behaviors, are correspondingly upregulated in these brain areas. Our results demonstrate that microglia are activated in specific brain sub-regions after CCI at delayed time points and imply that brain microglial activation plays a role in chronic pain-associated affective disorders.

Highlights

Neuropathic pain is a form of pathological chronic pain caused by injury or dysfunction of the nervous system that affects tens of millions of people worldwide (Goldberg and McGee, 2011; Raffaeli and Arnaudo, 2017)
After 1 week, the withdrawal threshold from mechanical stimuli measured by von Frey tests (Figure 1B) significantly decreased in the constriction injury (CCI)-induced mice compared to sham-control mice (0.2g vs. 0.9 g), demonstrating induction of mechanical allodynia
Eight weeks after CCI injury, time spent immobile significantly increased in both TST and forced swim test (FST), indicating that mice developed depressive-like behavior at a delayed time point

Summary

Introduction

Neuropathic pain is a form of pathological chronic pain caused by injury or dysfunction of the nervous system that affects tens of millions of people worldwide (Goldberg and McGee, 2011; Raffaeli and Arnaudo, 2017). Accumulating evidence indicates that spinal cord microglia play a critical role in the development of neuropathic pain (Tsuda et al, 2004; Coull et al, 2005; Beggs and Salter, 2010; Zhuo et al, 2011) According to this pathogenic model, injured nerve-derived signals induce activation of the spinal cord microglia and subsequent pain-related gene expression. This in turn sensitizes pain-transmitting neurons or neural circuits, resulting in central pain sensitization at the spinal cord level and neuropathic pain (Beggs et al, 2012; Ferrini and Koninck, 2013; Tsuda et al, 2013). Chronic neuropathic pain induced by peripheral nerve injury in animal models is accompanied by

Methods

Results

Conclusion