Modulation of morphine tolerance by Mas-related G protein-coupled receptor D signalling in the mouse dorsal root ganglion.

Summary

Time-resolved transcriptomics and in vivo manipulations identified a peripheral c‑Jun–Mrgprd–DS‑lncRNA–Ehmt2/G9a–Oprm1 pathway that drives morphine tolerance by reprogramming DRG gene expression. Suppressing Mrgprd delayed tolerance and increased MOR, whereas overexpression accelerated tolerance; targeting DS‑lncRNA/Ehmt2 reversed these effects.

Key Findings

• Acute morphine reduced DRG Mrgprd expression by ~70% at 6–24 h, normalizing by day 4.
• Mrgprd knockdown delayed, while AAV-Mrgprd overexpression accelerated, the development of morphine tolerance.
• Morphine decreased c-Jun (~40%); c-Jun directly bound the Mrgprd promoter (ChIP-qPCR/luciferase).
• Mrgprd knockdown increased Oprm1/MOR via DS-lncRNA upregulation and Ehmt2/G9a suppression; DS-lncRNA knockdown restored Ehmt2 and reinstated tolerance.

Clinical Implications

Although preclinical, the identified c‑Jun–Mrgprd–DS‑lncRNA–Ehmt2/G9a–Oprm1 axis suggests new targets to mitigate opioid tolerance, potentially sustaining analgesic efficacy and reducing dose escalation and adverse effects.

Limitations

• Preclinical mouse model; human translatability remains to be shown
• Pharmacologic tools targeting this axis and off-target effects were not clinically evaluated

Future Directions

Validate the axis in human DRG/tissue, develop selective modulators (e.g., Mrgprd or DS‑lncRNA/Ehmt2), and test efficacy/safety in large-animal models and early-phase clinical trials.