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When Pain Won’t Go Away

Things were so much simpler, or at least as far as the role of RNA is concerned, when I first took a biology class about a hundred years or so ago. We knew DNA carried our genetic information which through an intermediary, RNA, could be made into peptides, the building blocks of proteins. Compared to DNA or the proteins that carried out various cellular tasks, the role of RNA seemed dull because we thought RNA was essentially a copy of original genetic information from DNA (for more information as well as differences between DNA and RNA, go here)

About 20 years or so ago, however, we first learned that there was more to RNAs than met the eye. One group of small RNA molecules, justifiably called microRNAs or miRNA, for example, could act as enzymes, the biological catalysts that speed up biochemical reactions. Before, we thought only proteins could act as catalysts, so it came as a shock to biologists when we learned these small RNAs could also act as catalysts. A recent paper by Tramullas and colleagues not only underscores the importance of miRNA but also expand our understanding of neuropathy, which can cause numbness, tingling, weakness or pain. An example of neuropathy would be phantom limb syndrome where a person with an amputated arm could feel shooting pain from the amputated arm! Since I spent many years either being in pain or studying pain, I was curious to find out more about how miRNAs could be involved in neuropathy.
It all began with mice, or rather a specific transgenic/mutated mouse line that lacked a particular gene, BAMBI (morphogenetic protein and activin membrane-bound inhibitor). BAMBI is a decoy receptor for a member of proteins family that has been shown to have a protective role in neuropathic pain. Usually, when a ligand—TGF-β, in this case—binds to a receptor, a chain of chemical reactions takes place, but because BAMBI is not the actual receptor for TGF-β, nothing happens when TGF-β binds to BAMBI. However, binding to BAMBI lowers the availability of TFG-β because some of them would not be available to bind to their actual receptors (these would bind to BAMBI instead). So in this transgenic mouse line, the available quantity of TGF-β is greater than the normal mice with these pseudo receptors. Since TGF-β has a protective role in reducing neuropathic pain, it’s reasonable to expect that in BAMBI knock out mice, neuropathic pain would be less severe. 

To see if that happens to be the case, the authors introduced an injury to a nerve that caused neuropathy is normal mice, something that could be quantified by observing how much force one needs to apply before these injured mice withdrew their paws. The data shows that BAMBI knock-out mice didn’t develop neuropathy after the nerve injury—they only withdrew the paw after more pressure was applied to the paws compared to normal/wild type animals with a similar injury.
Since some earlier experiments had linked miRNAs with pain, the authors decided to determine if there are changes in miRNA levels in the mice that lacked BAMBI. They collected tissue samples from the spinal cord and then analyzed and compared with other control animals. They detected several aberrant levels of miRNAs, and among these, one particular miRNA, miR-30c-5p, stood out. The levels of this particular miRNA increased significantly in control animals, suggesting its role in neuropathic pain. They also found out that in rats, this miRNA was increased in several tissues that relay pain sensation. They subsequently used inhibitors to block this miRNA pharmacologically and found that inhibiting them prevented and reversed neuropathic pain. These results are encouraging, but how is TGF-β involved in this case?
To address this question, the authors decided to inject TGF-β protein in mice. Because we know TGF-β has a protective role against pain, we would expect the injured mice, injected with TGF-β, will not develop neuropathic pain, and that is exactly what the authors observed. Furthermore, miR-30c-5p levels didn’t increase in these mice. Taken together, these results underscore the involvement of both TGF-β and the miRNA in neuropathic pain. The authors also looked at miR-30c-5p levels in patients suffering from one type of neuropathy and saw increased levels of the miRNA in these patients. Furthermore, in some diabetic patients, levels of this miRNA predicted whether these patients also suffered from neuropathic pain or not: increased miRNA levels meant they also had neuropathic pain.
Taken together, this study suggests the involvement of a particular miRNA in specific cases of neuropathy. So can’t we just use an inhibitor for this miRNA to treat neuropathic pains? There are several problems with that idea. First, the study is specific to one kind of neuropathy, so we can’t assume that blocking this miRNA would alleviate pain in all patients suffering from neuropathies. Furthermore, in this study, the authors used only a small number of patients so follow-up studies will need to have a larger sample size before miRNA inhibitors can go for clinical trials. While that may sound slow, that is really how science works and should work: studies must be replicated before accepted as a general rule and even then, these general rules can be proven wrong. The involvement of microRNA in neuropathic pain is one of the examples that highlight how our understanding of RNA had evolved. And as for patients suffering from debilitating neuropathic pain, scientists are an inch closer to alleviating their suffering.

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