Emerging roles of miRNAs in neuropathic pain: From new findings to novel mechanisms

Abstract

Neuropathic pain, which results from damage to the somatosensory nervous system, is a global clinical condition that affects many people. Neuropathic pain imposes significant economic and public health burdens and is often difficult to manage because the underlying mechanisms remain unclear. However, mounting evidence indicates a role for neurogenic inflammation and neuroinflammation in pain pattern development. There is increasing evidence that the activation of neurogenic inflammation and neuroinflammation in the nervous system contribute to neuropathic pain. Altered miRNA expression profiles might be involved in the pathogenesis of both inflammatory and neuropathic pain by regulating neuroinflammation, nerve regeneration, and abnormal ion channel expression. However, the lack of knowledge about miRNA target genes prevents a full understanding of the biological functions of miRNAs. At the same time, an extensive study on exosomal miRNA, a newly discovered role, has advanced our understanding of the pathophysiology of neuropathic pain in recent years. This section provides a comprehensive overview of the current understanding of miRNA research and discusses the potential mechanisms of miRNAs in neuropathic pain.

Keywords: exosomes; miRNAs; neuroinflammation; neuropathic pain; review.

Figure 1

The classical bioformation process of miRNA. miRNAs are typically transcribed as primary miRNAs (pri-miRNAs) by RNA polymerase II (Pol II). The microprocessor complex, composed of the RNase III enzyme Drosha and the double-stranded RNA (dsRNA)-binding protein (dsRBP) DiGeorge critical region 8 (DGCR8), cleaves the pri-miRNA and releases a precursor miRNA (pre-miRNA). The export receptor exportin 5 binds pre-miRNAs and aids their export into the cytoplasm. Then the RNase III endonuclease DICER cleaves the pre-miRNA to release double-stranded miRNA. This miRNA is cleaved by Argonaute (Ago) to form the miRNA-induced silencing complex (miRISC).

Figure 2

MiRNAs in neuropathic pain. The following routes are used by miRNAs to mediate neuropathic pain in animals with damaged nerves: (1) operating on immune cells to stimulate the production of inflammatory cytokines through IRAK/TRAF6, TLR4/NF-κB, TXNIP/NLRP3, TGF-α/CCL2 and other pathways to regulate neuroinflammation; (2) accelerating axon regeneration by increasing the synthesis of trophic factors such BDNF, NGF, TGF-1, EGFR, and NT-3; (3) mediating neuroelectrophysiological changes by activating ion channels like Nav1.3, Nav1.7, Nav1.8, Kv1.2, TREK-1, Cav1.2-LTC, and Cav3.2.

Figure 3

Roles of exosomal miRNAs in neuropathic pain. Exosomal miRNAs can be transported to different sites after autocrine production, acting on macrophages, microglia, neurons or other tissue cells, and regulate the process of neuropathic pain by participating in the secretion of inflammatory factors, and oxidative stress, and regulating neural remodelling or nerve regeneration.

Figure 4

Relationship between exosomal miRNAs and axon regeneration. As one of the important cargos of exosomes, miRNAs are involved in mediating the process of axon regeneration. Exosomes produced by various stem cells enter neurons or glial cells through paracrine routes, where multiple miRNAs are released. Upregulation of exo-miR-219a-2-3p inhibits YY1 expression, thereby suppressing the NF-κB-p65 pathway and exerting neuroprotective effects. miR-199a-3p/145-5p suppresses Cblb and Cbl expression and causes upregulation of p-Erk and p-Akt, subsequently promoting neurite outgrowth. The miR-17-92 cluster and miR-21-5p carrying exosomes downregulate PTEN levels and subsequently activate the PI3K/Akt/mTOR signalling pathway, thereby increasing neuronal dendritic plasticity. MiR-181c-5p negatively regulates BIM mRNA, inhibits BIM expression level, reduces neuronal apoptosis, and promotes axon regeneration. Targeted inhibition of Nrf1 mRNA levels by miR-23b-39 subsequently promotes axonal regeneration.