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Updated: Jun 2, 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

A novel knock-in mouse reveals mechanistically distinct forms of morphine tolerance

Johan Enquist1, Joseph A Kim, Selena Bartlett

  • 1Ernest Gallo Clinic and Research Center, 5858 Horton St., Emeryville, CA 94608, USA.

The Journal of Pharmacology and Experimental Therapeutics
|May 13, 2011
PubMed

Insights

Investigating μ-opioid receptor (MOR) down-regulation in morphine tolerance, this study reveals that receptor degradation accelerates tolerance but reduces dependence. Wild-type MOR mice develop tolerance slower with less dependence and no receptor down-regulation.

Area of Science:

  • Pharmacology
  • Neuroscience
  • Molecular Biology

Background:

  • The role of μ-opioid receptor (MOR) down-regulation in the development of opioid tolerance is not fully understood.
  • Existing research presents conflicting findings regarding the direct link between MOR down-regulation and the extent of opioid tolerance.

Purpose of the Study:

  • To investigate how varying degrees of MOR down-regulation impact the development of morphine tolerance using a novel knock-in mouse model.
  • To differentiate between tolerance mediated by receptor down-regulation and other mechanisms of morphine tolerance.

Main Methods:

  • Generation of a novel knock-in mouse model expressing a mutant degrading MOR (DMOR) that is targeted for degradation upon internalization, unlike wild-type (WT) MOR.
  • Comparative analysis of morphine tolerance, dependence, and MOR expression levels between WT MOR and DMOR mice after morphine administration.
  • Assessment of receptor internalization and degradation following morphine activation in both WT and DMOR mice.

Main Results:

  • DMOR mice exhibited a more rapid onset of morphine tolerance accompanied by significant MOR down-regulation compared to WT MOR mice.
  • WT MOR mice developed morphine tolerance more slowly, and profound tolerance was observed without significant MOR down-regulation.
  • WT MOR mice displayed significantly higher morphine dependence, indicated by withdrawal symptoms, after long-term treatment compared to DMOR mice.

Conclusions:

  • Tolerance mediated by MOR down-regulation has distinct behavioral and biochemical manifestations compared to morphine tolerance in WT mice.
  • Receptor down-regulation is not a primary contributor to morphine tolerance in WT MOR mice.
  • Altering the extent of MOR down-regulation influences the development of morphine tolerance and dependence, suggesting distinct underlying mechanisms.

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