The emerging power and promise of non-coding RNAs in chronic pain

Abstract

Chronic pain (CP) is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage lasting longer than 3 months. CP is the main reason why people seek medical care and exerts an enormous economic burden. Genome-wide expression analysis has revealed that diverse essential genetic elements are altered in CP patients. Although many possible mechanisms of CP have been revealed, we are still unable to meet all the analgesic needs of patients. In recent years, non-coding RNAs (ncRNAs) have been shown to play essential roles in peripheral neuropathy and axon regeneration, which is associated with CP occurrence and development. Multiple key ncRNAs have been identified in animal models of CP, such as microRNA-30c-5p, ciRS-7, and lncRNA MRAK009713. This review highlights different kinds of ncRNAs in the regulation of CP, which provides a more comprehensive understanding of the pathogenesis of the disease. It mainly focuses on the contributions of miRNAs, circRNAs, and lncRNAs to CP, specifically peripheral neuropathic pain (NP), diabetic NP, central NP associated with spinal cord injury, complex regional pain syndrome, inflammatory pain, and cancer-induced pain. In addition, we summarize some potential ncRNAs as novel biomarkers for CP and its complications. With an in-depth understanding of the mechanism of CP, ncRNAs may provide novel insight into CP and could become new therapeutic targets in the future.

Keywords: biomarker; chronic pain; circular RNA; long non-coding RNA; microRNA; non-coding RNA.

FIGURE 1

Non-coding RNAs (ncRNAs) and their regulatory mechanism in chronic pain: ncRNAs can participate in pain regulation through various mechanisms. Some common and key mechanisms mainly include pain-related signaling pathways; pain-related receptors and targets; regulation of cytokines release; some cell processes (cell migration, autophagy and apoptosis etc.); exosomal ncRNAs crosstalk between cells and ncRNAs targeting ion channels related to chronic pain. Akt, V-akt murine thymoma viral oncogene homolog; Cav, voltage-gated calcium; IL, interleukin; MAPK, mitogen-activated protein kinases; Kv, voltage-gated potassium channel; Nav, voltage-dependent sodium; ncRNAs, Non-coding RNAs; PI3K, phosphatidylinositol-3-kinase; TLRs, toll-like receptors; TNF, tumor necrosis factor; TRPV1, transient receptor potential vanilloid 1.

FIGURE 2

Main functions of three types of non-coding RNAs. (A) General functions of microRNA (miRNA). Unwinding of the miRNA via Argonaute, and transactivation response RNA-binding protein (TRBP)-dependent loading into the RNA-induced silencing complex (RISC). Binding of target mRNAs to miRNAs in RISC can result in translation repression or degradation of the mRNA. MiRNA and RISC can translocate to other cells. The RISC contains RNA-binding proteins including protein kinase RNA activator, TRBP and Dicer. (B) General functions of circular RNA (circRNA). CircRNA can act as miRNA sponge and protein complex stabilization. CircRNAs have other functions (including promoting cell proliferation etc.). (C) General functions of Long non-coding RNA (lncRNA). LncRNA can inhibit miRNA and act as transcriptional regulator. LncRNA participates in scaffolding complexes. The lncRNA possesses different domains that bind distinct effector molecules. The lncRNA can bind its multiple effector partners at the same time, which may have transcriptional activating or repressive activities, together in both time and space. Ago, Argonaute; circRNAs, circular RNAs; lncRNAs, long non-coding RNAs; miRNAs, microRNAs; RISC, RNA-induced silencing complex; TRBP, transactivation response RNA-binding protein.

FIGURE 3

Distribution of dysregulated non-coding RNAs (ncRNAs) with the respective associated targets in diabetic neuropathic pain (DNP): ncRNAs (including microRNA, circular RNA, and long non-coding RNA) can participate in the development of DNP through various targets and mechanisms. NcRNAs displays different expressions in DRG, spinal cord and sciatic nerve of DNP models in DNP. DRG, dorsal root ganglion; HMGB1, high mobility group box-1; IL, interleukin; MAPK, mitogen-activated protein kinases; Nrf2, nuclear factor erythroid 2-related factor 2; RAP1A, Ras-associated protein-1 A; TNF, tumor necrosis factor; TRPV1, transient receptor potential vanilloid 1.