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. 2019 Dec 11;9(70):40895-40902.
doi: 10.1039/c9ra06264e. eCollection 2019 Dec 9.

Retracted Article: Upregulation of miR-26b alleviates morphine tolerance by inhibiting BDNF via Wnt/β-catenin pathway in rats

Xing Liu  1 , Jiefeng Geng  2 , Huilian Bu  1 , Junqi Ma  1 , Yanqiu Ai  1
Affiliations

Retracted Article: Upregulation of miR-26b alleviates morphine tolerance by inhibiting BDNF via Wnt/β-catenin pathway in rats

Xing Liu et al. RSC Adv. .

Retraction in

Abstract

Background: Morphine is a commonly used analgesic drug. However, long-term use of morphine will cause tolerance which limits its clinical application in pain treatment. MicroRNAs (miRNAs) have been reported to be involved in the morphine tolerance, but the underlying mechanism is still poorly understood. Methods: Tail flick test was used to measure the maximum possible effect (MPE). Quantitative real-time PCR was employed to detect miR-26b, BDNF, and Wnt5a expression in rat dorsal root ganglia (DRG). Luciferase report assay was introduced to verify the binding relationship between miR-26b and Wnt5a. BDNF, Wnt5a and β-catenin protein level were tested by western blotting. Results: MiR-26b was down-regulated during the development of morphine tolerance while BDNF was upregulated. Overexpression of miR-26b or BDNF inhibition alleviated morphine tolerance. Wnt5a was directly targeted and inhibited by miR-26b via binding to the 3'-UTR of Wnt5a. The Wnt/β-catenin pathway was active in morphine tolerant rats. Moreover, overexpression of Wnt5a could partially enhance miR-26 mimic-mediated morphine tolerance, while a Wnt5a inhibitor could attenuate the tolerance. Conclusion: The present study demonstrated that miR-26b overexpression alleviated morphine tolerance by inhibiting BDNF via the Wnt/β-catenin pathway in rats, highlighting a promising target for the treatment of morphine tolerance.

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Conflict of interest statement

No conflict of interest is declared by all named co-authors.

Figures

Fig. 1
Fig. 1. MiR-26b was down-regulated and BDNF was up-regulated in the dorsal root ganglia (DRG) of morphine-tolerant rats. Male and female SD rats were divided into 3 groups randomly (n = 6) and were injected with nothing (NC), saline (Sal, 10 μl) and morphine (Mor, 10 μg) twice a day for 7 days. (A) % MPE was calculated via tail flick test on 1, 3, 5, 7 days after treatment. (B) MiR-26b expression was measured by qRT-PCR on the indicated time point. (C) BDNF protein expression was determined by western blotting, with β-actin as the internal control. *P < 0.05.
Fig. 2
Fig. 2. Overexpression of miR-26b or BDNF knockdown partially reversed the morphine tolerance effect. (A and B) LV-miR-NC or LV-miR-26b was injected into the cord spinal of rats before morphine infection, followed by the detection of miR-26b expression level and % MPE on 1, 3, 5, 7 day. (C and D) Lentivirus stably transduced with sh-NC or sh-BDNF was injected into the cord spinal of rats before morphine infection, followed by the measurement of BDNF mRNA level and % MPE on 1, 3, 5, 7 day. *P < 0.05.
Fig. 3
Fig. 3. Wnt5a was a direct target of miR-26b. (A) Schematic of the position 1270–1277 for miR-26b binding site in the 3′-UTR of predicted by TargetScan and the mutated miR-26b-binding site. (B) Luciferase assay of Wnt5a-WT and Wnt5a-MUT with miR-26b in HEK293T cells. (C and D) BDNF, β-catenin and Wnt5a protein levels by western blotting in morphine-injected rats which were accompanied with miR-26b overexpression on day 7. *P < 0.05.
Fig. 4
Fig. 4. Wnt5a was involved in the miR-26b-mediated morphine tolerance. Female and male rats were separated into 4 groups randomly (n = 6): LV-miR-NC, LV-miR-26b, LV-miR-26b + LV-vector, LV-miR-26b + LV-Wnt5a. All of the rats are treated with morphine to develop the tolerance. (A) Relative Wnt5a mRNA expression on 1, 3, 5, 7 day in above 4 group rats. (B) % MPE of the 4 group rats during the development of morphine tolerance. *P < 0.05.
Fig. 5
Fig. 5. Wnt/β-catenin pathway was active in morphine tolerance. (A) β-catenin and Wnt5a protein expression by western blotting on day 7 after NC, saline and morphine treatment. (B) Gray scale of β-catenin and Wnt5a expression. *P < 0.05.
Fig. 6
Fig. 6. Wnt5a inhibitor alleviated the morphine tolerance. (A) BDNF, β-catenin and Wnt5a protein expression by western blotting on day 7 after morphine and IWR treatment. (B) Gray scale analysis of BDNF, β-catenin and Wnt5a protein expression. (C) % MPE in the IWR-1-endo + morphine and only morphine treated rats. *P < 0.05.
Fig. 7
Fig. 7. Schematic scheme of morphine tolerance via miR-26b. In rat morphine tolerance model, miR-26b was downregulated in the dorsal root ganglia. Then, low miR-26b level resulted in increased expression of BDNF and Wnt5a. Next, Wnt/β-catenin pathway was activated. Finally, BDNF overexpression and activated Wnt/β-catenin pathway enhanced morphine tolerance.
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