Anti-nociceptive action of peripheral muopioid receptors by G-beta-gamma protein-mediated inhibition of TRPM3 channels

Opioids, agonists of mu-opioid receptors (mu ORs), are the strongest pain killers clinically available. Their action includes a strong central component, which also causes important adverse effects. However, mu ORs are also found on the peripheral endings of nociceptors and their activation there produces meaningful analgesia. The cellular mechanisms downstream of peripheral mu ORs 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 mu OR 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 G beta gamma proteins, which form a complex with TRPM3. Accordingly, activation of peripheral mu ORs in vivo strongly attenuates TRPM3-dependent pain. Our data establish TRPM3 inhibition as important consequence of peripheral mu OR activation indicating that pharmacologically antagonizing TRPM3 may be a useful analgesic strategy.