Abstract
Delta (DOR) and mu opioid receptors (MOR) can complex as heteromers, conferring functional properties in agonist binding, signaling and trafficking that can differ markedly from their homomeric counterparts. Because of these differences, DOR/MOR heteromers may be a novel therapeutic target in the treatment of pain. However, there are currently no ligands selective for DOR/MOR heteromers, and, consequently, their role in nociception remains unknown. In this study, we used a pharmacological opioid cocktail that selectively activates and stabilizes the DOR/MOR heteromer at the cell surface by blocking its endocytosis to assess its role in antinociception. We found that mice treated chronically with this drug cocktail showed a significant right shift in the ED50 for opioid-mediated analgesia, while mice treated with a drug that promotes degradation of the heteromer did not. Furthermore, promoting degradation of the DOR/MOR heteromer after the right shift in the ED50 had occurred, or blocking signal transduction from the stabilized DOR/MOR heteromer, shifted the ED50 for analgesia back to the left. Taken together, these data suggest an anti-analgesic role for the DOR/MOR heteromer in pain. In conclusion, antagonists selective for DOR/MOR heteromer could provide an avenue for alleviating reduced analgesic response during chronic pain treatment.
Highlights
Delta and mu opioid receptors (DOR and MOR respectively) are inhibitory G-protein-coupled receptors that regulate pain transmission
Produce biased antagonism on DOR/MOR heteromers activated by methadone, whereby it selectively antagonizes endocytosis but not signal transduction from the DOR/MOR heteromer ([10], and see Figure S1A, B)
Because the DOR/MOR heteromer is rapidly degraded after endocytosis in response to methadone alone ([10], and see Figure S1C), we hypothesized that treatment with methadone alone would favor signaling from MOR homomers while co-treatment with methadone and NTB would stabilize the DOR/MOR heteromer, and thereby allow an assessment of the functional contribution of this heteromer to antinociception
Summary
Delta and mu opioid receptors (DOR and MOR respectively) are inhibitory G-protein-coupled receptors that regulate pain transmission. It was shown that thermal nociception is primarily modulated by MORs while mechanical nociception is primarily mediated by DOR [1], suggesting that these receptors are expressed in distinct circuits. Several lines of evidence indicate that the MOR and DOR modulate one another’s function in vivo [2,3,4], and there is mounting evidence that they can form heteromers with unique properties in vitro [5,6,7,8,9,10], and in vivo [11,12]. Deciphering the functional role of the DOR/MOR heteromer in pain transmission has been hindered by the lack of pharmacological agents selective for the heteromer over the MOR and/or DOR homomers
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