Noncoding RNAs: Novel Targets for Opioid Tolerance

Abstract

As a global health problem, chronic pain is one of the leading causes of disability, and it imposes a huge economic and public health burden on families and society. Opioids represent the cornerstone of analgesic drugs. However, opioid tolerance caused by long-term application of opioids is a major factor leading to drug withdrawal, serious side effects caused by dose increases, and even the death of patients, placing an increasing burden on individuals, medicine, and society. Despite efforts to develop methods to prevent and treat opioid tolerance, no effective treatment has yet been found. Therefore, understanding the mechanism underlying opioid tolerance is crucial for finding new prevention and treatment strategies. Noncoding RNAs (ncRNAs) are important parts of mammalian gene transcriptomes, and there are thousands of unique noncoding RNA sequences in cells. With the rapid development of high-throughput genome technology, research on ncRNAs has become a hot topic in biomedical research. In recent years, studies have shown that ncRNAs mediate physiological and pathological processes, including chromatin remodeling, transcription, posttranscriptional modification and signal transduction, which are key regulators of physiological processes in developmental and disease environments and have become biomarkers and potential therapeutic targets for various diseases. An increasing number of studies have found that ncRNAs are closely related to the development of opioid tolerance. In this review, we have summarized the evidence that ncRNAs play an important role in opioid tolerance and that ncRNAs may be novel targets for opioid tolerance.

Keywords: Noncoding RNA; chronic pain; circRNA; long noncoding RNA; microRNA; opioid tolerance.

Fig. (1)

Schematic diagram of the possible mechanisms by which ncRNAs participate in opioid tolerance. After long-term administration of opioids, abnormally expressed miRNAs and lncRNAs in the brain, spinal cord and DRG of mice/rats promoted the development of morphine tolerance. The let-7 family, miR-103/107 and miR-378-3p were highly expressed in the brain, leading to the downregulation of MOR and morphine tolerance. The MORs in the spinal cord were phosphorylated, and miR-365 was significantly downregulated, leading to the upregulation of β-arrestin-2 and its binding to MORs, which led to MOR uncoupling from G protein, MOR desensitization and morphine tolerance. Downregulation of miR-219-5p led to the upregulation of CaMKII γ and promoted the expression and activation of NMDA, and downregulation of miR-338 promoted the upregulation of CXCR4, leading to morphine tolerance. The upregulated lncRNA MRAK159688 in the spinal cord participated in morphine tolerance by promoting REST-mediated MOR downregulation. miR-146a, miR-124-3p and miR-223 were significantly downregulated in the spinal cord, mediating the high expression of TLR4, TRAF6 and NLRP3 downstream, respectively, and participating in the development of morphine tolerance. miR-873a-5p was involved in morphine tolerance by inhibiting A20 expression. Morphine-induced downregulation of miR-375 in the DRG activated the JAK2/STAT3 pathway to promote morphine tolerance. MOR: mu opioid receptor; CaMKII γ: calmodulin-dependent protein kinase II γ; NMDA: N-methyl-d-aspartic acid receptor; CXCR4: CXC chemokine receptor 4; TLR4: toll-like receptor 4; TRAF6: tumor necrosis factor receptor-associated factor 6; NLRP3: NOD-like receptor protein 3; STAT3: signal transducer and activator of transcription 3.