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Updated: Mar 16, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Morphine enhances IL-1β release through toll-like receptor 4-mediated endocytic pathway in microglia

Yongxin Liang1, Haichen Chu2, Yanan Jiang2

  • 1Department of Anesthesiology, The Affiliated Hospital of Qingdao University, 16 Jiangsu Road, Qingdao, 266071, China. liangzi66@hotmail.com.

Purinergic Signalling
|August 11, 2016
PubMed

Insights

Morphine triggers neuroinflammation by increasing interleukin-1β (IL-1β) via Toll-like receptor 4 (TLR4) and P2X4 receptor (P2X4R) pathways. TLR4 internalization drives IL-1β release, impacting morphine

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Morphine induces neuroinflammation and releases pro-inflammatory cytokines like interleukin-1β (IL-1β).
  • This neuroinflammatory response compromises morphine's analgesic effects and leads to tolerance.
  • Understanding the mechanisms of morphine-induced IL-1β release is crucial for managing opioid side effects.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying morphine-induced IL-1β synthesis and release in microglial cells.
  • To elucidate the roles of Toll-like receptor 4 (TLR4) and P2X4 receptor (P2X4R) signaling in this process.

Main Methods:

  • Microglial cells were treated with morphine (100 μM) daily for 3 days.
  • Analyzed TLR4 and P2X4R signaling using Western blot.
  • Measured IL-1β mRNA and protein levels via real-time RT-PCR and ELISA; assessed CD68 signaling with immunofluorescence.

Main Results:

  • Morphine significantly enhanced IL-1β synthesis and P2X4R protein expression.
  • TLR4 signaling was essential for morphine-induced IL-1β synthesis.
  • Morphine-induced IL-1β release was mediated by P2X4R and involved TLR4 endocytosis.

Conclusions:

  • Both TLR4 and P2X4R pathways are critical mediators of IL-1β synthesis and release in microglia following chronic morphine exposure.
  • TLR4 internalization represents a key mechanism driving morphine-induced microglial activation and subsequent IL-1β release.
Keywords:
Interleukin-1βMicrogliaMorphineP2X4 receptorsToll-like receptor 4

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