The μ-opioid receptor (MOR) agonist morphine is commonly used for pain management, but it has severe adverse effects and produces analgesic tolerance. Thus, alternative ways of stimulating MOR activity are needed. We found that MrgC11, a sensory neuron–specific G protein–coupled receptor, may form heteromeric complexes with MOR. Peptide-mediated activation of MrgC11 enhanced MOR recycling by inducing coendocytosis and sorting of MOR for membrane reinsertion. MrgC11 activation also inhibited the coupling of MOR to β-arrestin-2 and enhanced the morphine-dependent inhibition of cAMP production. Intrathecal coadministration of a low dose of an MrgC agonist potentiated acute morphine analgesia and reduced chronic morphine tolerance in wild-type mice but not in Mrg-cluster knockout (Mrg KO) mice. BAM22, a bivalent agonist of MrgC and opioid receptors, enhanced the interaction between MrgC11 and MOR and produced stronger analgesia than did the individual monovalent agonists. Morphine-induced neuronal and pain inhibition was reduced in Mrg KO mice compared to that in wild-type mice. Our results uncover MrgC11-MOR interactions that lead to positive functional modulation of MOR. MrgC shares genetic homogeneity and functional similarity with human MrgX1. Thus, harnessing this positive modulation of MOR function by Mrg signaling may enhance morphine analgesia in a sensory neuron–specific fashion to limit central side effects.

μ阿片受体（MOR）激动剂吗啡通常用于疼痛控制，但是它具有严重的副作用，并产生止痛耐受性。因此，需要刺激MOR活动的替代方法。我们发现MrgC11是一种感觉神经元特异性G蛋白偶联受体，可能与MOR形成异聚复合物。肽介导的MrgC11激活通过诱导共胞吞作用和MOR分选以重新插入膜，从而增强了MOR的回收利用。MrgC11激活还抑制了MOR与β-arrestin-2的偶联，并增强了吗啡依赖性cAMP的抑制作用。鞘内联合低剂量的MrgC激动剂可增强急性吗啡镇痛作用，并降低野生型小鼠的慢性吗啡耐受性，但对Mrg没有-群敲除（Mrg KO）小鼠。BAM22是MrgC和阿片样物质受体的二价激动剂，与单独的一价激动剂相比，它增强了MrgC11和MOR之间的相互作用，并产生更强的镇痛作用。与野生型小鼠相比，Mrg KO小鼠中吗啡诱导的神经元和疼痛抑制降低。我们的结果发现了MrgC11-MOR相互作用导致MOR的正功能调节。MrgC与人类MrgX1具有遗传同源性和功能相似性。因此，通过Mrg信号利用MOR功能的这种正调节作用可以以感觉神经元特异性的方式增强吗啡镇痛作用，以限制中枢性副作用。