Effect and mechanism of inhibition of PI3K/Akt/mTOR signal pathway on chronic neuropathic pain and spinal microglia in a rat model of chronic constriction injury

Abstract

ObjectiveTo explore the effects of inhibition of PI3K/Akt/mTOR signal pathway on chronic neuropathic pain (CNP) and spinal microglia in a rat model of chronic constriction injury (CCI).MethodsMale SD rats were assigned into control, sham, CCI, wortmannin, dimethyl sulfoxide (DMSO) and wortmannin-positive control groups. Paw withdrawal mechanical threshold (PWMT) and thermal withdrawal latency (TWL) were recorded. qRT-PCR and Western blotting were used to detect PI3K, Akt and mTOR expressions and their phosphorylation. OX-4 expression was detected by immunohistochemistry and glial fibrillary acidic protein (GFAP) and nerve growth factor (NGF) expressions by immunofluorescence.ResultsPWMT and TWL decreased in the CCI group than in the sham group on the 7th and 14th day after operation. Compared with the control and sham groups, the CCI group showed increased PI3K, Akt and mTOR mRNA expressions and elevated PI3K, p-Akt, p-mTOR and P70S6K protein expressions. More OX-42-positive cells and higher integrated optical density (IOD) of GFAP and NGF were found in the CCI group than the sham group at the 14th day after operation. Compared with the DMSO group, the wortmannin group had higher PWMT and TWL, decreased PI3K, Akt and mTOR mRNA expressions and reduced PI3K, p-Akt, p-mTOR and P70S6K protein expressions. Less OX-42-positive cells and lower IOD of GFAP and NGF were found in the wortmannin group than the DMSO group 14th day after operation.ConclusionInhibition of PI3K/Akt/mTOR signal pathway may alleviate CNP and reduce microglia and GFAP and NGF expressions in marrow in a rat model of CCI.

MiR-106b-5p represses neuropathic pain by regulating P2X4 receptor in the spinal cord in mice

“…The activated P2X 4 R causes the phosphorylation of p38-MAPK, and the release of BDNF, all of which are essential to the persistence of pain hypersensitivity after nerve injury. Mounting evidence suggests that P2X 4 R may regulate the progress of neuropathic pain through the p38MAPK, ERK1/2, and PI3K/Akt pathways, which were core pathways in the development of neuropathic pain [11,[40][41][42]. Meanwhile, miR-106b could promote cervical cancer progression by modulating the expression of the GSK3B, VEGFA, and PTK2 genes.…”

RNA expression preoperatively and postoperatively following total knee replacement: a pilot study in patients with and without chronic postsurgical pain

“…Analysis of RNA gene expression of peripheral blood leukocytes from patients with chronic masticatory myalgia demonstrated that the MAPK signaling pathway was upregulated 23. PI3K-AKT-mTOR signaling pathway is involved in the activation of microglia cells and progression of chronic nerve pain 24. BDNF, synthesized in the primary sensory neurons, is anterogradely transported to the central terminals of the primary afferents in the spinal dorsal horn, where it is involved in the modulation of painful stimuli 25.…”

Manganese-enhanced MRI depicts a reduction in brain response to nociception by mTOR inhibition in chronic pain rats

“…Modulation of chronic pain through mTOR inhibition is a newly studied application target for chronic pain control [16,36]. Previous studies have observed changes in chronic pain through the inhibition of mTOR signaling in the spinal cord [37][38][39][40], and recent studies have demonstrated effective modulation of chronic pain by direct mTOR signaling control in the brain [16,41], The activation of mTOR regulates protein synthesis by phosphorylating downstream effectors, which in uence a wide range of physiological and pathological states including neuropathic, in ammatory, and cancer-related pain [16][17][18], The Torin1 and XL388 used in this study were ATP-competitive inhibitors that suppress the phosphorylation of downstream effectors to regulate mRNA translation and protein synthesis [42].…”