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Updated: Dec 21, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Melatonin alleviates morphine analgesic tolerance in mice by decreasing NLRP3 inflammasome activation

Qianjin Liu1, Ling-Yan Su2, Chunli Sun3

  • 1Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China; Kunming College of Life Science, University of Chinese Academy of Sciences, Kunming, Yunnan, 650204, China.

Redox Biology
|May 16, 2020
PubMed

Insights

Melatonin pretreatment reduces morphine tolerance by blocking NLRP3 inflammasome activation in mice. This suggests combining melatonin with morphine may improve pain relief and reduce side effects in patients.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Long-term morphine use for chronic pain leads to analgesic tolerance and hyperalgesia.
  • Current treatments for these morphine side effects are ineffective.
  • The NLRP3 inflammasome is implicated in pain and inflammation.

Purpose of the Study:

  • To investigate the role of the NLRP3 inflammasome in morphine tolerance and hyperalgesia.
  • To determine if melatonin can mitigate morphine-induced side effects.
  • To explore the potential of combining melatonin and morphine for pain management.

Main Methods:

  • Morphine administration in wild-type and Nlrp3-deficient mice.
  • Melatonin pretreatment and co-administration with morphine.
  • Assessment of analgesic tolerance and hyperalgesia.
  • Measurement of NLRP3 inflammasome activation (NLRP3, IL-1β) in brain and blood.
  • siRNA knockdown and pharmacological inhibition of NLRP3.
  • Analysis of serum IL-1β and melatonin levels in heroin-addicted patients.

Main Results:

  • Morphine treatment significantly activated the NLRP3 inflammasome in the prefrontal cortex and peripheral blood of mice.
  • Melatonin pretreatment blocked morphine-induced NLRP3 inflammasome activation.
  • Nlrp3 deficiency attenuated morphine-induced analgesic tolerance and hyperalgesia.
  • Co-administration of melatonin and low-dose morphine enhanced analgesia and reduced inflammasome activity.
  • Heroin-addicted patients showed elevated IL-1β and reduced melatonin levels.

Conclusions:

  • NLRP3 inflammasome activation, mediated by microglia, is a key mechanism underlying morphine tolerance and hyperalgesia.
  • Melatonin effectively inhibits NLRP3 inflammasome activation, mitigating morphine's detrimental effects.
  • Combined melatonin and morphine therapy holds promise for improved pain management and reduced side effects, warranting clinical trials.
Keywords:
Analgesic toleranceMelatoninMorphineNLRP3 inflammasomePain

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