Since the discovery of microRNAs, these small ribonucleotides have been implicated in a broad range of cellular processes1. MicroRNAs typically work as inhibitory gate-keepers to keep the expression of numerous genes in check1. 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 neurons2, a recent study suggests that microRNAs may actually work as pain neurotransmitters. The study is published in the April 2014 issue of Neuron3.
The study was conducted by a team of scientists lead by Dr. Ru-Rong Ji at the Duke Medical Research Centre at Durham, NC. The study reveals that the microRNA, let7b, is actively expressed by nociceptive (pain-sensing) neurons, and is released into the extracellular space in response to pain stimuli such as formalin. Further investigating the effects of secreted let7b on a series of nociceptive neuronal cultures, Ji discovers that let7b can trigger the transmission of pain signals (in the form of electrical currents dubbed action potentials) in nociceptive neurons.
Ji further shows that let7b does not affect the expression of genes involved in pain transmission, including pain receptors such as TLR7, TRPA1 and TRPV1- molecules that trigger pain signals in response to pain stimuli. Rather, he demonstrates that let7b works like a pain neurotransmitter that can physically bind to pain receptors to trigger 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 is not seen in transgenic mice that lack the expression of TLR7 and TRPA1 receptors. Overall, these studies demonstrate that let7b is indeed a functional pain neurotransmitter.
As an extension of this study, Ji also shows that let7b contains a unique sequence motif (the GUUGUGU motif) that is recognized by immune receptors, including the TLR7 pain receptor. 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 fail to activate TLR7, and have no effects 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.
<!--[if !supportLists]-->1. <!--[endif]-->Bartel, D. P. Cell. 136, 215–233 (2009)
<!--[if !supportLists]-->2. <!--[endif]-->Zhao J. et al. J. Neurosci. 30, 10860–10871 (2010)
<!--[if !supportLists]-->3. <!--[endif]-->Park C.-K. et al. Neuron 82, 47–54 (2014).