A recent publication in Science has touched on the importance of miRNA in regulating major processes in our neuronal system. This paper published by Ernfors group from the Karolinska Institute in Sweden has identified miRNA-183 (miR-183) as an important regulator of neuropathic pain. I found it quite interesting as it highlights the essential, and novel role of miRNA in how we sense pain.
The way how we sense pain can vary depending on our genetic makeup, and during neuropathic pain, mechanical allodynia involves “hypersensitivity of nociceptive neurons and recruitment of touch-activated low-threshold mechanoreceptive LTMR neurons into the nociceptive network”.
Previous research had identified the miRNA-183 cluster is important in regulating pain – over-expression reverse chronic pains, while downregulation causes pain. Emfors group in this paper identified the location of transduction and where miRNA acts on during neuropathy.
In a conditional knockout of miRNA-183 deficient in all neurons, the group found that mice are more susceptible to mechanical pain. This pain is reversible by a marketed drug, called gabapentin (also known as Neurontin), that is commonly used to treat epilepsy, neuropathic pain and hot flashes.
The group then started to tease out the targets of miR-183 cluster. They identified 18 up-regulated and 15 down-regulated genes, when comparing dorsal root ganglia from conditional KO and control mice in RNAseq. mRNA of Cacna2d1 and -2d2 of pain sensitivity by regulating calcium channel are of interest, as they were both increased in the KO mice. They hypothesized that the dysregulation (deletion) of miR183 cluster leads to increase of 2d1 and 2d2, and that lead to neuropathy (in this case, hypersensitivity to mechanical stimuli)
SNI-induced dystonia was found to correlate with higher response to mechanical stimuli when they delete miR-183 cluster specifically in the LTMR neurons, which can be reversed by Gabapentin. This state was also associated with an increased expression of 2d1 and 2d2. This means that these LTMR neurons could produce pain during neuropathy that can be reversed by gabapentin.
I guess the big question is how this could be translated into attenuating neuropathic pain in humans. The perception of pain is greatly influenced by our genetic makeup. Identification of specific SNPs in miR-183 cluster that are associated with pain-related disease could be of interest. Using miR-183 to target Cd1 and Cd2 and its targeted genes could be also used as a therapy, however it is unclear how we can specifically target miR-183 on the neurons that matter.
miRNA-based technology and therapeutics still seems to be relatively early. There definitely seems to be great disruptive potential as a potential therapy. But there is certainly concerns regarding understanding its targets and delivery mechanism. Here are the clinical trials ongoing with miRNA: