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Updated: Sep 16, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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SIRT1-mediated deacetylation and activation of MEK/ERK pathway decreased IL-6 in spinal dorsal horn to promote

Shenghui Hu1, Fengjia Zhou1, Baoguang Lin1

  • 1Department of Radiotherapy, General Hospital of Northern Theater Command, Shenyang, China.

Neuropharmacology
|July 5, 2025
PubMed

Insights

Sirtuin 1 (SIRT1) plays a key role in opioid tolerance. Reduced SIRT1 levels promote oxycodone tolerance by increasing IL-6 expression via histone modification and MEK/ERK pathway activation.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Molecular Biology

Background:

  • Opioid analgesics like oxycodone are limited by tolerance development.
  • Sirtuin 1 (SIRT1), a histone deacetylase, is investigated for its role in this process.

Purpose of the Study:

  • To elucidate the role of SIRT1 in oxycodone-induced analgesic tolerance.
  • To identify molecular mechanisms underlying tolerance development.

Main Methods:

  • Established oxycodone tolerance in adult ICR mice using the tail-flick test.
  • Utilized RT-qPCR, Western blotting, and ChIP-qPCR to analyze gene and protein expression.
  • Assessed levels of SIRT1, IL-6, histone acetylation, and MEK/ERK pathway components.

Main Results:

  • Oxycodone administration led to analgesic tolerance and reduced SIRT1 levels in the spinal cord.
  • Elevated IL-6 expression, increased H3K9ac at the IL-6 promoter, and activated MEK/ERK signaling were observed.
  • An SIRT1 agonist (SRT1720) reversed tolerance, suppressed IL-6, and normalized molecular markers.

Conclusions:

  • SIRT1 is crucial in promoting oxycodone tolerance.
  • SIRT1 facilitates tolerance by deacetylating H3K9 at the IL-6 promoter, upregulating IL-6 via the MEK/ERK pathway.
Keywords:
DeacetylationIL-6MEK/ERKOxycodone toleranceSIRT1

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