Influence of Phosphatidylinositol-3-Kinase/Protein Kinase B-Mammalian Target of Rapamycin Signaling Pathway on the Neuropathic Pain Complicated by Nucleoside Reverse Transcriptase Inhibitors for the Treatment of HIV Infection

Abstract

Background:Nucleoside reverse transcriptase inhibitors (NRTIs) are the earliest and most commonly used anti-human immunodeficiency virus drugs and play an important role in high active antiretroviral therapy. However, NRTI drug therapy can cause peripheral neuropathic pain. In this study, we aimed to investigate the mechanisms of rapamycin on the pain sensitization of model mice by in vivo experiments to explore the effect of mammalian target of rapamycin (mTOR) in the pathogenesis of neuropathic pain caused by NRTIs.Methods:Male Kun Ming (KM) mice weighing 20–22 g were divided into control, 2 mg/kg rapamycin, 12 mg/kg stavudine, and CMC-Na groups. Drugs were orally administered to mice for 42 consecutive days. The von Frey filament detection and thermal pain tests were conducted on day 7, 14, 21, 28, 35, and 42 after drug administration. After the last behavioral tests, immunohistochemistry and western blotting assay were used for the measurement of mTOR and other biomarkers. Multivariate analysis of variance was used.Results:The beneficial effects of rapamycin on neuropathic pain were attributed to a reduction in mammalian target of rapamycin sensitive complex 1 (mTORC1)-positive cells (70.80 ± 2.41 vs. 112.30 ± 5.66, F = 34.36, P < 0.01) and mTORC1 activity in the mouse spinal cord. Mechanistic studies revealed that Protein Kinase B (Akt)/mTORsignaling pathway blockade with rapamycin prevented the phosphorylation of mTORC1 in stavudine-intoxicated mice (0.72 ± 0.04 vs. 0.86 ± 0.03, F = 4.24, P = 0.045), as well as decreased the expression of phospho-p70S6K (0.47 ± 0.01 vs. 0.68 ± 0.03, F = 6.01, P = 0.022) and phospho-4EBP1 (0.90 ± 0.04 vs. 0.94 ± 0.06, F = 0.28, P = 0.646).Conclusions:Taken together, these results suggest that stavudine elevates the expression and activity of mTORC1 in the spinal cord through activating the Akt/mTOR signaling pathway. The data also provide evidence that rapamycin might be useful for the treatment of peripheral neuropathic pain.

Progress in Pathological and Therapeutic research of HIV-related Neuropathic Pain

“…D4T increased the expression and activity of mTORC1 in the spinal cord by activating the Akt/mTOR signaling pathway. In contrast, rapamycin can reverse D4T-induced mechanical hyperalgesia by inhibiting the mTOR signaling pathway and reducing mTORC1 activity, suggesting that the Akt/mTOR signaling pathway is involved in HRNP (Cheng & Wu, 2018).…”

Modulation of mTORC1 Signaling Pathway by HIV-1

“…Mitochondrial toxicity can lead to the inhibition of late stages of autophagy mediated by active mTORC1 signaling, as shown for zidovudine (NRTI) in myocytes [137]. Another study demonstrated that stavudine (NRTI) could activate mTORC1 signaling in a mouse model of peripheral neuropathic pain [138]. Treatment with rapamycin attenuates persistent neuropathic pain in mice.…”

Recent Advances in Pain Management: Relevant Protein Kinases and Their Inhibitors

“…The use of inhibitors such as SH-6 [ 96 ] ( Figure 22 ) demonstrated the involvement of PKB/Akt in mechanical hypersensitivity [ 97 ]. More recently, Cheng et al studied the role of phosphatidylinositol 3-kinase (PI3K)/PKB/mTOR signaling pathway in neuropathic pain caused by nucleoside reverse transcriptase inhibitors in HIV treatment [ 98 ].…”