Review The Role of miRNAs in Neuropathic Pain, 2023, Morchio et al

Abstract
Neuropathic pain is a debilitating condition affecting around 8% of the adult population in the UK. The pathophysiology is complex and involves a wide range of processes, including alteration of neuronal excitability and synaptic transmission, dysregulated intracellular signalling and activation of pro-inflammatory immune and glial cells. In the past 15 years, multiple miRNAs–small non-coding RNA–have emerged as regulators of neuropathic pain development. They act by binding to target mRNAs and preventing the translation into proteins. Due to their short sequence (around 22 nucleotides in length), they can have hundreds of targets and regulate several pathways.

Several studies on animal models have highlighted numerous miRNAs that play a role in neuropathic pain development at various stages of the nociceptive pathways, including neuronal excitability, synaptic transmission, intracellular signalling and communication with non-neuronal cells. Studies on animal models do not always translate in the clinic; fewer studies on miRNAs have been performed involving human subjects with neuropathic pain, with differing results depending on the specific aetiology underlying neuropathic pain. Further studies using human tissue and liquid samples (serum, plasma, saliva) will help highlight miRNAs that are relevant to neuropathic pain diagnosis or treatment, as biomarkers or potential drug targets.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10045079/

 

I think this is an interesting paper for a few reasons.

One is that it talks about miRNAs, and specifically, miR-448, which was recently found to be elevated in a sample of people with ME/CFS.

Another is that it presents some mechanisms by which pain can become chronic (in contrast to the psychogenic 'magic' hypothesis).

 

We know of course that just having a study suggesting a link doesn't mean there is one, but it looks as though things have moved further than that with respect to miRNA and pain.



The key idea is shown in that picture. The loop of the hairpin shaped miRNA is snipped off to activate it. One side of the hairpin locks onto messenger RNA, stopping transcription.

So, there are those three ways that microRNAs are thought to cause pain:

• neuronal excitability - interfering with the firing across axons. MicroRNAs alter the operation of ion channels.
• intracellular signalling
• interaction with non-neuronal cells

Neuronal excitability
Here's an example for volted gate sodium channels:

Here's an example for calcium channels. It's interesting to note that calcium channels can regulate long term changes in gene expression, causing neuronal sensitisation. And a micro-RNA is downregulated after nerve injury - applying the micro-RNA down-regulates the calcium channels and so reduces pain sensitisation.

Potassium channels too can be affected. They are responsible for allowing a neuron to return to a resting state after firing. MicroRNAs targeting potassium channels have been found to be upregulated after nerve injury:

There are more examples.

 

Synaptic transmission
As well as neuronal excitability, miRNAs can change the way the signal is transmitted to the next neuron. For example, a chemotherapy drug upregulated an miRNA, which reduced an enzyme necessary for the production of GABA. The GABA was needed for inhibiting the signal. So the drug resulted in an increase in pain signals, via the increase in the miRNA.

They might also be causing neuronal cell death:

Intracellular signalling
There are lots of examples of this sort of impact. Here's one:

Two miRNAs are upregulated after a chronic constriction injury, reducing the expression of a G-protein coupled receptor and so increasing the activation of p38 and the subsequent expression of inflammatory molecules.

and another, also increasing p38 activation: