Diabetic neuropathic pain induced by streptozotocin alters the expression profile of non‑coding RNAs in the spinal cord of mice as determined by sequencing analysis

Abstract

Diabetic neuropathic pain (DNP) is one of the most serious complications of diabetes. Patients with DNP always exhibit spontaneous and stimulus-evoked pain. However, the pathogenesis of DNP remains to be fully elucidated. Non-coding RNAs (ncRNAs) serve important roles in several cellular processes and dysregulated expression may result in the development of several diseases, including DNP. Although ncRNAs have been suggested to be involved in the pathogenesis of DNP, their precise roles remain to be determined. In the present study, sequencing analysis was used to investigate the expression patterns of coding genes, microRNAs (miRNAs), long ncRNAs (lncRNAs) and circular RNAs (circRNAs) in the spinal cord of mice with streptozotocin (STZ)-induced DNP. A total of 30 mRNAs, 148 miRNAs, 9 lncRNAs and 135 circRNAs exhibited significantly dysregulated expression 42 days after STZ injection. Functional enrichment analysis indicated that protein digestion and absorption pathways were the most significantly affected pathways of the differentially expressed (DE) mRNAs. The Rap1 signaling pathway, human T-lymphotropic virus-I infection and the MAPK signaling pathway were the three most significant pathways of the DE miRNAs. A total of 2,118 distinct circRNAs were identified and the length of the majority of the circRNAs was <1,000 nucleotides (nt) (1,552 circRNAs were >1,000 nt) with a median length of 620 nt. In the present study, the expression characteristics of coding genes, miRNAs, lncRNAs and circRNAs in DNP mice were determined; it paves the road for further studies on the mechanisms associated with DNP and potentially facilitates the discovery of novel ncRNAs for therapeutic targeting in the management of DNP.

Emerging roles of circular RNAs in neuropathic pain

“…Recently, He et al performed RNA sequencing to study the expression patterns of circRNAs, lncRNAs and miRNAs in the spinal cord of streptozotocin‐induced diabetic neuropathic pain (DNP) mice. 52 They found that there were 135 circRNAs were differentially expressed and 71 circRNAs were downregulated and 64 circRNAs were overexpressed in spinal cord between control group and DNP group. Amongst these, circ_0010794, circ_0006623, circ_0006175, circ_0007095, circ_0005297, circ_0012840 and circ_0001580 was overexpressed and circ_0016083, circ_0006471, circ_0008757, circ_0004843 and circ_0013996 was downregulated (Figure 1 and Table 1 ).…”

The etiological roles of miRNAs, lncRNAs, and circRNAs in neuropathic pain: A narrative review

“…In the spinal cord, numerous miRNA expression changes have been observed in chronic constriction injury (CCI) and diabetic neuropathic pain (DNP) rodents. [23][24][25][26] Previous research has suggested some miRNAs may be related to neuropathic pain development, for example, miR-500, -221, and -21, 25 thus, acting as potential targets in its treatment. 27 Cytoscape software constructed the miRNA-target gene regulatory network in the supraspinal region, including the nucleus accumbens (NAc), medial prefrontal cortex, and periaqueductal gray, between SNI and sham rats.…”

“…The spinal cord dorsal horn relays and modulates pain signals from the peripheral nociceptors to the supraspinal regions. In the spinal cord, numerous miRNA expression changes have been observed in chronic constriction injury (CCI) and diabetic neuropathic pain (DNP) rodents 23–26 . Previous research has suggested some miRNAs may be related to neuropathic pain development, for example, miR‐500, ‐221, and ‐21, 25 thus, acting as potential targets in its treatment 27 …”

DNA Methylation and Non-Coding RNAs during Tissue-Injury Associated Pain

“…With this technique, Xiong and colleagues were able to identify a total of 374 circRNA differentially expressed in the DRG of rats following the induction of neuropathic pain by CCI (preprint here: [ 55 ]). This approach has also been used to identify differentially expressed miRNA, lncRNAs and circRNAs in the spinal cord of a model of diabetic neuropathic pain [ 59 ]; lncRNAs and mRNA in the spinal cord of rats subjected to paclitaxel-induced peripheral neuropathy [ 52 ]; and miRNA and mRNA in the DRG of rats between a CCI group and a CCI-exercise group [ 73 ]. However, RNA-Seq techniques may suffer from PCR-related bias, including library preparation and sequencing errors [ 161 ].…”