MicroRNA-16 Alleviates Inflammatory Pain by Targeting Ras-Related Protein 23 (RAB23) and Inhibiting p38 MAPK Activation

Abstract

BackgroundThe purpose of our study was to determine the functional role of microRNA (miR)-16 in chronic inflammatory pain and to disclose its underlying molecular mechanism.Material/MethodsInflammatory pain was induced by injection of complete Freund’s adjuvant (CFA) to Wistar rats. The pWPXL-miR-16, PcDNA3.1- Ras-related protein (RAB23), and/or SB203580 were delivered intrathecally to the rats. Behavioral tests were detected at 0 h, 4 h, 1 d, 4 d, 7 d, and 14 d after CFA injection. After behavioral tests, L4–L6 dorsal spinal cord were obtained and the levels of miR-16, RAB23, and phosphorylation of p38 (p-p38) were evaluated by quantitative real-time PCR (qRT-PCR). In addition, luciferase reporter assay was performed to explore whether RAB23 was a target of miR-16, and qRT-PCR and Western blotting were used to confirm the regulation between RAB23 and miR-16.ResultsThe level of miR-16 was significantly decreased in the CFA-induced inflammatory pain. Intrathecal injection of miR-16 alleviates pain response and raised pain threshold. The level of RAB23 was significantly increased in the pain model, and intrathecal injection of RAB23 aggravated pain response. Luciferase reporter assay confirmed that RAB23 was a direct target of miR-16, and RAB23 was negatively regulated by miR-16. In addition, we found that simultaneous administration of SB203580 and miR-16 further alleviates pain response compared to only administration of miR-16.ConclusionsOur findings suggest that miR-16 relieves chronic inflammatory pain by targeting RAB23 and inhibiting p38 MAPK activation.

Hypomethylation of nerve growth factor (NGF) promotes binding of C/EBPα and contributes to inflammatory hyperalgesia in rats

“…The CFA-induced inflammatory pain model is one of the commonly used animal models of chronic inflammatory pain as the mechanical allergy induced by CFA can last for quite a long time, and our experimental results showed in Fig. 1 were consistent with the previous reports [11,[20][21][22]. Some studies reported that CFA injection can significantly increase histone deacetylase HDACs expression and induce inflammatory pain, while the HDAC blockers can significantly alleviate CFAinduced inflammatory pain [23,24].…”

“…They can bind to the 3′-untranslated region (3′-UTR) region of target mRNAs to regulate gene expression [8]. Recent studies showed that multiple miRNAs are involved in inflammatory pain, such as miR-451 may relieve chronic inflammatory pain through inhibiting microglia activation-mediated inflammation by targeting TLR4 [9], miRNA-219 expression level significantly reduced in CFA-induced chronic inflammation pain in mice model [10], and miR-16 involved in relief of chronic inflammatory pain by targeting RAB23 and inhibiting p38 MAPK activation [11].…”

Upregulation of CXCR4 through promoter demethylation contributes to inflammatory hyperalgesia in rats

“…19 Currently, there are two commonly used inflammatory pain models: One is CFA inflammatory pain model, which can be maintained for a long time and relatively stable. [20][21][22] The other is the BV inflammatory pain model by injection of bee venom to plantar subcutaneous site, which is applied to study the pathophysiological mechanism of persistent inflammatory pain. 23 In this study, we chose the classic CFA inflammatory pain model to study the expression characteristics of CXCR4.…”

MicroRNA‑16 inhibits interleukin‑13‑induced inflammatory cytokine secretion and mucus production in nasal epithelial cells by suppressing the IκB kinase β/nuclear factor‑κB pathway

“…In this study, we identified a large number of miRNAs that were significantly deregulated in nasal mucosal tissues from AR patients using miRNA microarray. Among them, miR-16 was one of the most downregulated miRNAs and also reported to play different roles in inflammatory diseases (20,21). Thus, we chose miR-16 for further study.…”

“…1A). Among the aberrantly expressed miRNAs, miR-16 was one of the top downregulated miRNAs in nasal mucosal tissues and altered expression of miR-16 has been found to play a critical role in inflammation in several types of diseases (20,21). We also measured its expression in 25 pairs of the nasal mucosal tissues among AR patients and NAR control group by qRT-PCR and observed that miR-16 was significantly decreased in AR group compared with NAR control group (Fig.…”