Institut für Physiologie und Pathophysiologie, Philipps-Universität Marburg, Marburg, Germany.
Max-Planck-Institut für Experimentelle Medizin, Göttingen, Germany.
Elife. 2017 Aug 15;6:e26280. doi: 10.7554/eLife.26280.
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.
阿片类药物是μ-阿片受体（μORs）的激动剂，是临床上最有效的止痛药。它们的作用包括强烈的中枢成分，这也会导致重要的不良反应。然而，μORs 也存在于伤害感受器的外周末梢，它们在那里的激活产生有意义的镇痛作用。外周 μOR 下游的细胞机制尚不清楚。在这里，我们在小鼠背根神经节的神经元中表明，存在于伤害感受器外周部分的促伤害性 TRPM3 通道被 μOR 激活强烈抑制，比同一部位的其他 TRP 通道（如 TRPV1 和 TRPA1）抑制得更厉害。TRPM3 通道的抑制是通过涉及 Gβγ 蛋白的短信号级联反应发生的，Gβγ 蛋白与 TRPM3 形成复合物。因此，体内外周 μOR 的激活强烈减弱了依赖于 TRPM3 的疼痛。我们的数据确立了 TRPM3 抑制作为外周 μOR 激活的重要后果，表明药理学拮抗 TRPM3 可能是一种有用的镇痛策略。
