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Updated: Sep 23, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
Published on: July 29, 2014
Pinocembrin alleviates chronic morphine-induced analgesic tolerance and hyperalgesia by inhibiting microglial
Dongfeng Han1, Weiping Dong1, Wei Jiang1
1Department of Anesthesiology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Background:
Chronic opioid induced analgesic tolerance is a major obstacle in pain management. Microglial activation is involved in morphine tolerance and pinocembrin suppresses microglial activation in several disease models. We aim to investigate whether and how pinocembrin alleviates morphine tolerance.
Methods:
We induced chronic morphine tolerance in mice by daily morphine injection, with some mice receiving pinocembrin. Analgesic tolerance and hyperalgesia were determined by behavioral assays. The effects of pinocembrin on morphine induced microglial activation, neuroinflammation, and STAT3 activation were determined by Iba1 immunostaining, Il1b and Tnfa mRNA levels and STAT3 phosphorylation. Finally, the effects of STAT3 inhibition on chronic morphine tolerance were assessed.
Results:
We show that pinocembrin not only suppressed but also reversed preexisting chronic morphine tolerance and hyperalgesia. We found that chronic administration of morphine lead to microglial activation and neuroinflammation, which were suppressed by pinocembrin. Our results reveal a strong connection of STAT3 with morphine tolerance and pinocembrin suppressed morphine-induced STAT3 activation both in vivo and in BV2 cells. Finally, we show that STAT3 inhibition is sufficient to suppress morphine tolerance and hyperalgesia.
Conclusion:
Our study suggests that pinocembrin effectively prevents and alleviates chronic morphine tolerance through inhibition of STAT3 mediated microglia activation and neuroinflammation.
Insights
Pinocembrin effectively prevents and reverses chronic morphine tolerance by inhibiting microglial activation and neuroinflammation via STAT3 signaling. This offers a potential new strategy for pain management.
Area of Science:
- Neuroscience
- Pharmacology
- Immunology
Background:
- Chronic opioid-induced analgesic tolerance is a significant challenge in pain management.
- Microglial activation plays a role in morphine tolerance.
- Pinocembrin is known to suppress microglial activation in various disease models.
Purpose of the Study:
- To investigate if pinocembrin can alleviate morphine tolerance.
- To elucidate the mechanism by which pinocembrin affects morphine tolerance.
Main Methods:
- Chronic morphine tolerance was induced in mice.
- Behavioral assays were used to assess analgesic tolerance and hyperalgesia.
- Effects on microglial activation, neuroinflammation, and STAT3 activation were analyzed.
Main Results:
- Pinocembrin suppressed and reversed existing morphine tolerance and hyperalgesia.
- Morphine-induced microglial activation and neuroinflammation were reduced by pinocembrin.
- Pinocembrin inhibited STAT3 activation, and STAT3 inhibition alone suppressed morphine tolerance.
Conclusions:
- Pinocembrin prevents and alleviates chronic morphine tolerance.
- The mechanism involves the inhibition of STAT3-mediated microglial activation and neuroinflammation.
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