Research ArticlePain

Oligomerization of MrgC11 and μ-opioid receptors in sensory neurons enhances morphine analgesia

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Science Signaling  19 Jun 2018:
Vol. 11, Issue 535, eaao3134
DOI: 10.1126/scisignal.aao3134

A better way to use opioids?

Morphine and other opioids are excellent at reducing pain, but they have behavioral side effects and are addictive. He et al. found that the analgesic response to morphine could be enhanced by compounds that activate the peripheral sensory neuron–localized receptor MrgC11 in mice and MrgX in human cells. Activation of MrgC11 promoted its interaction with the opioid receptor MOR, which directed MOR’s intracellular signaling toward a G protein–mediated pathway that promoted its quick recycling to the cell surface. This enabled the use of lower doses of morphine to achieve pain relief in mice, without the tolerance and locomotor effects typically associated with morphine. These findings suggest that coactivating MrgX in patients may improve the use of opioids for treating pain.


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.

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