mu-Opioid receptor down-regulation and cAMP-dependent protein kinase phosphorylation in a mouse model of chronic

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Updated: Oct 29, 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

M A Bernstein1, S P Welch

  • 1Department of Pharmacology and Toxicology, Medical College of Virginia, Virginia Commonwealth University, Richmond, VA 23298, USA.

Brain Research. Molecular Brain Research
|June 24, 1998
PubMed

Insights

Morphine tolerance involves changes in mu-opioid receptors. Chronic morphine reduces receptor levels and alters phosphorylation, suggesting structural changes contribute to tolerance.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Morphine tolerance is a significant clinical challenge.
  • Mu-opioid receptor (MOR) down-regulation and phosphorylation are implicated in tolerance.
  • Understanding these molecular changes is crucial for developing effective pain management strategies.

Purpose of the Study:

  • To investigate the correlation between antinociception and changes in MOR quantity and phosphorylation state in an animal model of morphine tolerance.
  • To quantify MOR protein levels and assess receptor phosphorylation following acute and chronic morphine administration.

Main Methods:

  • Utilized a mouse model of morphine tolerance.
  • Quantified mu-opioid receptor protein using Western immunoassay in brainstem tissue.
  • Assessed receptor phosphorylation state via immunoprecipitation and back-phosphorylation assays.

Main Results:

  • Acute morphine administration did not alter mu-receptor quantity.
  • Chronic morphine administration led to a 50% reduction in mu-receptor protein levels compared to placebo.
  • Receptor phosphorylation showed an initial decrease followed by a naloxone-reversible increase correlating with antinociception after acute morphine.
  • Chronic morphine resulted in decreased cAMP-dependent protein kinase A (PKA)-induced mu-receptor phosphorylation.

Conclusions:

  • Mu-opioid receptor down-regulation occurs with chronic morphine exposure.
  • Altered mu-receptor phosphorylation, particularly reduced PKA-induced phosphorylation, is associated with morphine tolerance.
  • These molecular alterations suggest a potential structural or conformational change in the mu-opioid receptor in the morphine-tolerant state.

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