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Updated: Aug 14, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Trifluoperazine, an orally available clinically used drug, disrupts opioid antinociceptive tolerance

Lei Tang1, Pradeep K Shukla, Zaijie Jim Wang

  • 1Department of Biopharmaceutical Sciences, College of Pharmacy, University of Illinois, 833 South Woods Street, Chicago, IL 60612, USA.

Neuroscience Letters
|December 29, 2005
PubMed

Insights

Trifluoperazine reversed and prevented morphine tolerance in mice by inhibiting Calcium/calmodulin dependent protein kinase II (CaMKII) activity. This suggests trifluoperazine could treat opioid tolerance and addiction.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Opioid tolerance reduces pain relief and increases addiction risk.
  • Calcium/calmodulin dependent protein kinase II (CaMKII) is implicated in opioid tolerance.

Purpose of the Study:

  • To investigate trifluoperazine's effects on morphine tolerance in mice.
  • To explore the role of CaMKII inhibition in this process.

Main Methods:

  • Mice received trifluoperazine acutely or as pretreatment before morphine administration.
  • Antinociceptive tolerance and CaMKII activity were measured.

Main Results:

  • Trifluoperazine completely reversed established morphine tolerance.
  • Trifluoperazine significantly attenuated the development of tolerance.
  • Trifluoperazine abolished morphine-induced CaMKII up-regulation.

Conclusions:

  • Trifluoperazine suppresses opioid tolerance, likely by inhibiting CaMKII.
  • Trifluoperazine warrants further study for treating opioid tolerance and addiction in humans.

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