MiR-873a-5p Targets A20 to Facilitate Morphine Tolerance in Mice.

Jiangju Huang,Xia Liang,Zhuofeng Ding,Yan Kong,Wangyuan Zou,Zengli Zhang,Zongbin Song,Qulian Guo,Jian Wang

doi:10.3389/fnins.2019.00347

Abstract

Long-term morphine administration leads to tolerance and a gradual reduction in analgesic potency. Noncoding microRNAs (miRNAs) modulate gene expression in a posttranscriptional manner, and their dysregulation causes various diseases. Emerging evidence suggests that miRNAs play a regulatory role in the development of morphine tolerance. In the present study, we hypothesized that miR-873a-5p is a key functional small RNA that participates in the development and maintenance of morphine tolerance through the regulation of A20 (tumor necrosis factor α-induced protein 3, TNFAIP3) in mice. We measured the percentage of maximum possible effect (MPE %) to evaluate the analgesic effect of morphine. The expression of miR-873a-5p and its target gene A20 were determined after the morphine-tolerant model was successfully established. Intrathecal injection with lentivirus to intervene in the expression of A20 and the miR-873a-5p antagomir was used to explore the role of miR-873a-5p in the development of morphine tolerance. Chronic morphine administration significantly increased the expression of miR-873a-5p, which was inversely correlated with decreased A20 expression in the spinal cord of morphine-tolerant mice. Downregulation of miR-873a-5p in the spinal cord attenuated and partly reversed the development of morphine tolerance accompanied by overexpression of A20. Similarly, A20 was upregulated by a recombinant lentivirus vector, which attenuated and reversed the pathology of morphine tolerance by inhibiting the activation of nuclear factor (NF)-κB. Collectively, our results indicated that miR-873a-5p targets A20 in the spinal cord to facilitate the development of morphine tolerance in mice. Downregulating the expression of miR-873a-5p may be a potential strategy to ameliorate morphine tolerance.

Highlights

Morphine is often used to treat a variety of acute and chronic pain conditions (Bohn et al, 2000)
Compared with the expression in the NS group, the expression of miR-873a-5p in the MT group began to increase on day 3 after morphine administration and was significantly higher on day 7 (NS vs. MT, n = 6, P < 0.05; Figures 1B,C), correlating with the development of morphine tolerance
To investigate the A20 protein expression level in the spinal cord of morphine-tolerant mice, Western blot analysis was conducted and showed that A20 expression was gradually decreased after morphine administration, especially after mice were administered morphine over 7 days (NS vs. MT, n = 4, P < 0.05; Figure 1D)

Summary

Introduction

Morphine is often used to treat a variety of acute and chronic pain conditions (Bohn et al, 2000). The analgesic application of morphine is limited by undesirable effects such as morphine tolerance, drug dependence and respiratory depression (Harrison et al, 1998; Eriksen et al, 2006; Song et al, 2012). Morphine tolerance is defined as an attenuated analgesic effect, and an increasing morphine dosage is required to achieve adequate analgesia for long-term application (Song et al, 2010). Increasing evidence has shown that morphine tolerance is a complex process involving miR-873a-5p Facilitates Morphine Tolerance some cellular adaptations and molecular mechanisms (Arttamangkul et al, 2018). The underlying cellular and molecular mechanisms of morphine tolerance are not entirely understood. Recent research found that miR-873 inhibits morphine-induced macrophage apoptosis, which may provide new molecular mechanisms for morphine addiction. The relationship between miR-873a-5p and morphine tolerance is unclear

Methods

Results

Discussion

Conclusion