Since the discovery of microRNAs, these small ribonucleotides have been implicated in a broad range of cellular processes(1). MicroRNAs typically work as inhibitory gate-keepers to keep the expression of numerous genes in check(1). They do so by binding to the 3’ untranslated region of target messenger RNAs (mRNAs) that encode specific genes, and consequently preventing the translation of these mRNAs into their corresponding protein products.
Interestingly enough, it turns out that microRNAs may not necessarily work by suppressing gene expression. For example, unlike the previous concept suggesting that microRNAs control pain perception by turning off genes (such as ion channels) that influence the excitability of pain-sensing neurons(2), a recent study suggests that microRNAs may actually work as pain neurotransmitters. The study is published in the April 2014 issue of Neuron(3).
In this study, Dr. Ru-Rong Ji and his team at the Duke Medical Research Centre at Durham, NC discovered a microRNA, let7b, that is actively released by nociceptive (pain sensing) neurons in response to pain stimuli such as formalin. Further investigating the effects of secreted let7b on a series of nociceptive neuronal cultures, Ji demonstrates that let7b can trigger the transmission of pain signals (in the form of electrical currents referred to as action potentials) in nociceptive neurons.
Ji further shows that let7b does not affect the expression of genes involved in pain neurotransmission, including pain receptors such as TLR7, TRPA1 and TRPV1- receptors that trigger pain signals in response to pain stimuli. Rather, he demonstrates that let7b works like a pain neurotransmitter that can physically bind to these pain receptors, and that the binding triggers the downstream transmission of pain signals in nociceptive neurons. Indeed, the injection of let7b into the mouse paw can elicit a pain response in normal mice, and that this effect was not seen in transgenic mice that lack the expression of TLR7 and TRPA1 pain receptors.
As an extension of this study, Ji also shows that let7b contains a unique sequence motif (the GUUGUGU motif) that is recognized by the TLR7 pain receptors. This unique sequence is shared by other microRNAs such as miRNA-599, which is shown in this study to stimulate pain signals in nociceptive neurons through TLR7 activation. Importantly, microRNAs that lack the GUUGUGU motif failed to activate the TLR7 pain receptors, and had no effect on pain neurotransmission.
By demonstrating the unexpected role of microRNAs as a pain neurotransmitter, and by identifying the specific sequence motif required for microRNAs to function as pain neurotransmitters, Ji has inadvertently discovered a new class of pain neurotransmitters. The discovery of microRNAs as a new molecular player in nociception can provide an additional dimension in our understanding of pain perception. Because microRNAs are short sequences that can be easily manipulated or inhibited, the study also points to an exciting new chapter in the development of pain killers.
1. Bartel, D. P. Cell. 136, 215–233 (2009)
2. Zhao J. et al. J. Neurosci. 30, 10860–10871 (2010)
3. Park C.-K. et al. Neuron 82, 47–54 (2014).