Moritz Bünemann, Eleonora Zakharian, Julia Stab, Paulina Nuñez-Badinez, Christian Goecke, Dominik Oliver, Julia Sondermann, Raissa Enzeroth, Marlene Schmidt, Alejandro Cohen, Jochen Schwenk, Johannes Oberwinkler, Wolfgang Greffrath, Franziska M Schneider, Florian Mohr, Sandeep Dembla, Manuela Schmidt, Bernd Nürnberg, Stephan E. Philipp, Michael G. Leitner, Marc Behrendt, and Publica
Opioids, agonists of µ-opioid receptors (µORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, µORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral µORs are not well understood. Here, we show in neurons of murine dorsal root ganglia that pro-nociceptive TRPM3 channels, present in the peripheral parts of nociceptors, are strongly inhibited by µOR activation, much more than other TRP channels in the same compartment, like TRPV1 and TRPA1. Inhibition of TRPM3 channels occurs via a short signaling cascade involving Gβγ proteins, which form a complex with TRPM3. Accordingly, activation of peripheral µORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral µOR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy., eLife digest There are very few treatments available for people suffering from strong or long-lasting pain. Currently, substances called opioids – which include the well-known drug morphine – are the strongest painkillers. However, these drugs also cause harmful side effects, which makes them less useful. Like all drugs, opioids mediate their effects by interacting with molecules in the body. In the case of opioids, these interacting molecules belong to a group of receptor proteins called G-protein coupled receptors (or GPCRs for short). These opioid receptors are widely distributed in the nerve cells and brain regions that detect and transmit pain signals. It was poorly understood how activation of opioid receptors reduces the activity of pain-sensing nerve cells, however several lines of evidence had suggested that a protein called TRPM3 might be involved. TRPM3 is a channel protein that allows sodium and calcium ions to enter into nerve cells by forming pores in cell membranes, and mice that lack this protein are less sensitive to certain kinds of pain. Dembla, Behrendt et al. now show that activating opioid receptors on nerve cells from mice, with morphine and a similar substance, rapidly reduces the flow of calcium ions through TRPM3 channels. Further experiments confirmed that activating opioid receptors in a mouse’s paw also reduced the pain caused when TRPM3 proteins are activated. GPCRs interact with a group of small proteins called G-proteins that, when activated by the receptor, split into two subunits. Based on studies with human kidney cells, Dembla, Behrendt et al. found the so-called G-beta-gamma subunit then carries the signal from the opioid receptor to TRPM3. Two independent studies by Quallo et al. and Badheka, Yudin et al. also report similar findings. These new findings show that drugs already used in the treatment of pain can indirectly alter how TRPM3 works in a dramatic way. These results might help scientists to find drugs that work in a more direct way to dial down the activity of TRPM3 and to combat pain with fewer side effects. Though first it will be important to confirm these new findings in human nerve cells.