The slightest touch can evoke intense pain in patients suffering from nerve injuries or conditions such as diabetic neuropathy. A team of researchers of the Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) has found a way to suppress pain in mice by applying a newly identified chemical agent to the skin of the animals. The substance blocked the action of an ion channel in nerves which is responsible for the perception of light touch. The activation of this channel also leads to severe pain after injuries, which the substance eliminated. The method could work in humans.
An anesthetic injection like that given by a dentist numbs all feeling in the surrounding tissue. This is often the only approach for treating people who suffer from a painful hypersensitivity that often accompanies nerve damage. Anesthetics that shut down all the functions of mechanosensory nerves reduce pain, but they also prevent other important signals from getting through.
Suppressing pain from mechanical stimuli without disturbing other sensations
Using the EU OPENSCREEN screening platform, which is jointly operated by the MDC and the Leibniz-Institut für Molekulare Pharmakologie (FMP), Cécile-Vogt fellow Dr. Kate Poole, Dr. Christiane Wetzel and their colleagues in the research team of Prof. Gary Lewin at the MDC and the Charité – Universitätsmedizin Berlin have now identified a substance that suppresses pain from mechanical stimuli without disturbing other sensations.
Very light touch is detected by a molecular sensor in the skin, an ion channel called “Piezo2”. Such channels are like tiny valves in the membranes of neurons which open once they experience stress from movement in the skin. When open, electrically charged particles pass through the valve. This creates an electrical signal which the cell then amplifies and forwards to the spine. The protein STOML3 tunes the mechanical sensitivity of Piezo2 ion channel.
A new substance which prevents Stoml3 from forming clusters und suppresses mechanical sensation
The researchers subjected the STOML3 protein to a drug screen, testing 35,000 different chemicals in large-scale in vitro experiments. They identified a substance called OB-1 which prevents STOML3 from forming clusters and thereby inhibits its function. Further electrochemical measurements of cells confirmed that when this didn’t happen, the Piezo2 ion channel remained closed.
Most importantly, the chemical effectively suppressed only this type of mechanical sensation in mice without affecting other types of sensation. Under the influence of OB-1, the animals’ sensitivity to light touch was significantly reduced. After the effects of the drug had worn off, the animals’ sensitivity returned to normal levels. “Colleagues at the MDC designed a set of behavioral experiments in which the animals could ‘talk’ to us,” Lewin says. “Small amounts of the substance were administered to the mouse paw. The paw was then gently tapped. The mice had been trained to reach for a reward when they felt it.
The OB-1 drug had a dramatic effect on animals suffering from touch-evoked pain caused by nerve injuries or diabetes. Treating the skin with OB-1 completely eliminated this type of pain. This indicates that its cause might be an increase in STOML3’s modulation of Piezo2, which means that dampening it would be a way of treating the condition.
A major step in treating neuropathic pain?
“The results are encouraging for many reasons,” Prof. Lewin says. “What this represents is a new strategy that arose from understanding the mechanisms that turn sensations of touch into pain. From what we can tell so far, the substance only affects a very specific type of mechanoreceptor that has both STOML3 proteins and Piezo2 channels. It dampens the perception of painful stimuli in a way that doesn’t affect other signals that the animal needs. And the effects are reversible.”
Prof. Lewin says that developing the substance into a treatment will be a long process. But at some point it should be ready for trials in people. If human patients respond the same way, this will represent a major step in treating a neuropathology that has a devastating effect on the lives of many people.
Christiane Wetzel1,10, Simone Pifferi1,9, Cristina Picci1,2, Caglar Gök1, Diana Hoffmann1,3, Kiran K Bali4, André Lampe5, Liudmila Lapatsina1, Raluca Fleischer1, Ewan St John Smith1,6, Valérie Bégay1, Mirko Moroni1, Luc Estebanez1,3, Johannes Kühnemund1, Jan Walcher1, Edgar Specker5, Martin Neuenschwander5, Jens Peter von Kries5, Volker Haucke5, Rohini Kuner4, James F A Poulet1,3, Jan Schmoranzer7, Kate Poole1,8,10 & Gary R Lewin1,3 (2016): „Small-molecule inhibition of STOML3 oligomerization reverses pathological mechanical hypersensitivity.“ Nature Neuroscience.
1Department of Neuroscience, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany. 2Department of Biomedical Sciences, Section of Cytomorphology, University of Cagliari, Monserrato (California), Italy. 3Neuroscience Research Center and Cluster of Excellence NeuroCure, Charité – Universitätsmedizin, Berlin, Germany. 4Institute of Pharmacology, Heidelberg University, Heidelberg, Germany. 5Leibniz-Institut für Molekulare Pharmakologie (FMP), Berlin, Germany. 6Department of Pharmacology, University of Cambridge, Cambridge, UK. 7Freie Universität Berlin, Berlin, Germany. 8Department of Physiology and EMBL Australia Node for Single Molecule Science, School of Medical Sciences, UNSW, Sydney, Australia. 9Present address: Neurobiology Group, SISSA, International School for Advanced Studies, Trieste, Italy. 10These authors contributed equally to this work. Corresponding authors: Gary R. Lewin and Kate Poole.
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