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Updated: Jul 9, 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

Tolerance to repeated morphine administration is associated with increased potency of opioid agonists

Susan L Ingram1, Tara A Macey, Erin N Fossum

  • 1Department of Psychology, WSU Vancouver, Vancouver, WA 98686, USA. ingram@vancouver.wsu.edu

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
|November 30, 2007
PubMed

Insights

Opioid tolerance involves complex changes in mu-opioid receptors. Repeated morphine administration in rats enhances receptor response but leads to faster desensitization, contributing to tolerance.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Pain Research

Background:

  • Opioid tolerance limits the clinical efficacy of pain relievers.
  • Cellular mechanisms of morphine tolerance, particularly mu-opioid receptor desensitization, remain unclear.
  • Periaqueductal gray (PAG) neurons are crucial for morphine's pain-relieving effects and tolerance development.

Purpose of the Study:

  • To investigate the cellular mechanisms of mu-opioid receptor desensitization in the PAG of morphine-tolerant rats.
  • To understand the biphasic effects of opioids on G-protein-mediated inwardly rectifying potassium (GIRK) currents in the PAG.

Main Methods:

  • Electrophysiological recordings of GIRK currents in PAG neurons from morphine-tolerant and saline-pretreated rats.
  • Concentration-response curves for met-enkephalin (ME)-induced currents.
  • Assessment of current desensitization kinetics and blockade with mu-opioid receptor antagonist beta-funaltrexamine (beta-FNA).

Main Results:

  • Morphine tolerance potentiated ME-induced GIRK currents, indicated by a leftward shift in the concentration-response curve (EC50=281 nM in tolerant vs. 8.8 microM in saline rats).
  • Beta-funaltrexamine (beta-FNA) inhibited these currents, confirming mu-opioid receptor involvement.
  • Despite enhanced initial potentiation, peak GIRK currents in tolerant rats desensitized significantly more (56%) than in saline-pretreated rats (15%) over 10 minutes.

Conclusions:

  • Repeated morphine administration enhances mu-opioid receptor agonist potency and coupling to G-proteins in the PAG.
  • This enhanced signaling paradoxically leads to accelerated desensitization of GIRK currents.
  • Increased mu-opioid receptor desensitization in the PAG is a key cellular mechanism underlying antinociceptive tolerance.

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