Korean J Pain.  2021 Apr;34(2):176-184. 10.3344/kjp.2021.34.2.176.

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

Affiliations
  • 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

Abstract

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.

Keyword

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