Anxiolytic effect of GABAergic neurons in the anterior cingulate cortex in a rat model of chronic inflammatory pain

Yi Liang,Dan-ning Xi,Jun-ying Du,Meng-ting Qiu,Xiao-mei Shao,Xiao-ming Jin,Jun-fan Fang,Si-si Wang,Fang-bing Shao,Jing-gen Liu,Zui Shen,Jian-qiao Fang

doi:10.1186/s13041-021-00849-9

Abstract

Chronic pain easily leads to concomitant mood disorders, and the excitability of anterior cingulate cortex (ACC) pyramidal neurons (PNs) is involved in chronic pain-related anxiety. However, the mechanism by which PNs regulate pain-related anxiety is still unknown. The GABAergic system plays an important role in modulating neuronal activity. In this paper, we aimed to study how the GABAergic system participates in regulating the excitability of ACC PNs, consequently affecting chronic inflammatory pain-related anxiety. A rat model of CFA-induced chronic inflammatory pain displayed anxiety-like behaviors, increased the excitability of ACC PNs, and reduced inhibitory presynaptic transmission; however, the number of GAD65/67 was not altered. Interestingly, intra-ACC injection of the GABAAR agonist muscimol relieved anxiety-like behaviors but had no effect on chronic inflammatory pain. Intra-ACC injection of the GABAAR antagonist picrotoxin induced anxiety-like behaviors but had no effect on pain in normal rats. Notably, chemogenetic activation of GABAergic neurons in the ACC alleviated chronic inflammatory pain and pain-induced anxiety-like behaviors, enhanced inhibitory presynaptic transmission, and reduced the excitability of ACC PNs. Chemogenetic inhibition of GABAergic neurons in the ACC led to pain-induced anxiety-like behaviors, reduced inhibitory presynaptic transmission, and enhanced the excitability of ACC PNs but had no effect on pain in normal rats. We demonstrate that the GABAergic system mediates a reduction in inhibitory presynaptic transmission in the ACC, which leads to enhanced excitability of pyramidal neurons in the ACC and is associated with chronic inflammatory pain-related anxiety.

Highlights

Chronic inflammatory pain is one of the major problems that affects the quality of life of patients
We observed painrelated behavior at base and 1 days, 7 days, 14 days, 21 days and days after the injection according to Paw withdrawal thresholds (PWTs) and anxiety-like behavior from to 32 days according to Open field test (OF), Elevated zero maze test (EZM), Novelty suppressed feeding test (NSF) and Marble‐burying test (MBT) results (Fig. 1A)
Twenty-eight days after complete Freund’s adjuvant (CFA) injection, the rats displayed multiple anxiety-like behaviors, including in the OF test (P < 0.01, Fig. 1C), the EZM test (P < 0.01, Fig. 1D), the NSF test (P < 0.01, Fig. 1F), and the MBT (P < 0.01, Fig. 1E)

Summary

Introduction

Chronic inflammatory pain is one of the major problems that affects the quality of life of patients. The treatment of chronic inflammatory pain is still a considerable challenge in clinical practice. Chronic pain leads to concomitant mood disorders, such as anxiety and depression, and morbidity ranges from 20 to 40% in chronic pain patients [5, 6], which make the mechanism. Shao et al Mol Brain (2021) 14:139 underlying chronic inflammatory pain much more complex. Negative emotion threatens the quality of life of chronic pain patients far more than chronic pain does in some cases. It is important to explore the mechanism of chronic inflammatory painrelated negative emotion to provide patients with better treatment options

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Conclusion