pISSN 2005-9159
eISSN 2093-0569

Experimental Research Article

Korean J Pain 2021; 34(2): 176-184

Published online April 1, 2021 https://doi.org/10.3344/kjp.2021.34.2.176

Copyright © The Korean Pain Society.

Inflammatory cytokines in midbrain periaqueductal gray contribute to diabetic induced pain hypersensitivity through phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway

Mochi Guo1 , Zongming Jiang1 , Yonghao Chen2 , Fei Wang3 , Zhifeng Wang4

1Department of Anesthesia, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang, China
2Department of Anesthesia, Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, Jiangsu, China
3Bioinformation Branch, Hangzhou Hibio Bioinformation Technology Company Hang Zhou, Hangzhou, Zhejiang, China
4Department of Anesthesia, Shaoxing Second Hospital, Shaoxing, Zhejiang, China

Correspondence to:Zhifeng Wang
Department of Anesthesia, Shaoxing Second Hospital, 123 Yanan Road, Yuecheng District of Shaoxing City, Shaoxing, Zhejiang 312000, China
Tel: +86-10-575-88229212
Fax: +86-10-575-88229286
E-mail: jixueyang1980@163.com

Handling Editor: Jong Yeon Park

*These authors contributed equally to this work as co-first authors.

Received: November 9, 2020; Revised: December 22, 2020; Accepted: December 24, 2020

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.


Background: Diabetes-related neuropathic pain frequently occurs, and the underpinning mechanism remains elusive. The periaqueductal gray (PAG) exhibits descending inhibitory effects on central pain transmission. The current work aimed to examine whether inflammatory cytokines regulate mechanical allodynia and thermal hyperalgesia induced by diabetes through the phosphoinositide 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) pathway in the PAG.
Methods: Streptozotocin (STZ) was administered intraperitoneally to mimic allodynia and hyperalgesia evoked by diabetes in rats. Behavioral assays were carried out for determining mechanical pain and thermal hypersensitivity. Immunoblot and ELISA were performed to examine PAG protein amounts of interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α), as well as their corresponding receptors in STZ rats, and the expression of PI3K/protein kinase B (Akt)/mTOR signaling effectors.
Results: Increased PAG p-PI3K/p-Akt/p-mTOR protein amounts were observed in STZ-induced animals, a PI3K-mTOR pathway inhibition in the PAG attenuated neuropathic pain responses. Moreover, the PAG concentrations of IL-1β, IL-6, and TNF-α and their receptors (namely, IL-1R, IL-6R, and tumor necrosis factor receptor [TNFR] subtype TNFR1, respectively) were increased in the STZ rats. Additionally, inhibiting IL-1R, IL-6R, and TNFR1 ameliorated mechanical allodynia and thermal hyperalgesia in STZ rats, alongside the downregulation of PI3K-mTOR signaling.
Conclusions: Overall, the current study suggests that upregulated proinflammatory cytokines and their receptors in the PAG activate PI3K-mTOR signaling, thereby producing a de-inhibition effect on descending pathways in modulating pain transmission, and eventually contributing to neuropathic pain.

Keywords: Cytokines, Diabetes Mellitus, Hyperalgesia, Mesencephalon, Neuralgia, Pain Threshold, Periaqueductal Gray, Phosphatidylinositol 3-Kinases, Streptozocin, TOR Serine-Threonine Kinases.