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Updated: Jul 11, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
07:23

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

Published on: July 29, 2014

RGS14 prevents morphine from internalizing Mu-opioid receptors in periaqueductal gray neurons

María Rodríguez-Muñoz1, Elena de la Torre-Madrid, Gema Gaitán

  • 1Neurofarmacología, Instituto de Neurobiología Santiago Ramón y Cajal, Madrid E-28002, Spain.

Cellular Signalling
|September 11, 2007
PubMed

Insights

Morphine causes desensitization by preventing mu-opioid receptor (MOR) internalization, unlike DAMGO. Silencing RGS14 protein in mice promotes MOR phosphorylation and internalization, reducing morphine tolerance.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Opioid agonists vary in their ability to stimulate mu-opioid receptor (MOR) endocytosis.
  • Opioid-induced tolerance is linked to receptor phosphorylation and internalization.
  • Morphine causes desensitization with minimal MOR internalization, unlike DAMGO.

Purpose of the Study:

  • To investigate the role of RGS14 protein in MOR desensitization and tolerance to morphine.
  • To elucidate the mechanisms underlying differential MOR regulation by various opioid agonists.

Main Methods:

  • Utilized mouse models with RGS14 protein knockdown.
  • Examined MOR phosphorylation at specific residues (e.g., serine 375) using GRK substrates.
  • Assessed MOR internalization and recycling via receptor trafficking.
  • Investigated the involvement of calcium/calmodulin-dependent kinase II (CaMKII) in MOR desensitization.

Main Results:

  • RGS14 silencing in mice increased MOR serine 375 phosphorylation, leading to enhanced receptor internalization and recycling.
  • Silencing RGS14 resulted in resensitization to morphine and reduced tolerance development.
  • Morphine, but not DAMGO, activated CaMKII in naive mice, contributing to plasma membrane MOR desensitization.
  • In RGS14 knockdown mice, morphine failed to activate CaMKII.

Conclusions:

  • RGS14 protein acts as a negative regulator, preventing GRK phosphorylation of MORs and subsequent beta-arrestin-mediated endocytosis.
  • Phosphorylation and internalization of MORs disrupt CaMKII-mediated negative regulation, impacting opioid receptor signaling.
  • Differential MOR trafficking and associated signaling pathways explain the distinct tolerance profiles of various opioid agonists.

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