Related Experiment Video

Updated: May 14, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities

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NETs activate the GAS6-AXL-NLRP3 axis in macrophages to drive morphine tolerance

Qingyan Tian1, Haiyue Guo1, Mengyao Zhang1

  • 1Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, 211166, China.

Cell Communication and Signaling : CCS
|April 11, 2025
PubMed
Abstract

Insights

Neutrophil extracellular traps (NETs) drive morphine tolerance by activating the GAS6-AXL-TLR7/9 pathway. Disrupting NETs or this axis offers a novel strategy to manage pain effectively.

Area of Science:

  • Immunology
  • Pharmacology
  • Pain Research

Background:

  • Morphine tolerance is a significant clinical obstacle in managing severe pain.
  • Understanding the molecular mechanisms of morphine tolerance is crucial for developing effective treatments.

Purpose of the Study:

  • To investigate the role of neutrophil extracellular traps (NETs) in the development of morphine tolerance.
  • To elucidate the specific molecular pathways involved in NETs-mediated morphine tolerance.
  • To identify potential therapeutic targets for combating morphine tolerance.

Main Methods:

  • Evaluation of morphine tolerance in C57BL/6J mice using the tail-flick test.
  • Investigation of NETs formation and macrophage engulfment via Western blotting, real-time PCR, ELISA, and confocal microscopy.
  • Assessment of the GAS6-AXL-TLR7/9-NLRP3 inflammasome pathway and cytokine production (IL-1β, IL-18).

Main Results:

  • Elevated NETs levels were observed in patients and animals experiencing morphine tolerance.
  • Genetic or pharmacological disruption of NETs formation significantly alleviated morphine tolerance.
  • Morphine-induced NETs are engulfed by macrophages via the GAS6-AXL axis, activating the TLR7/9-NLRP3 inflammasome and increasing IL-1β/IL-18, contributing to tolerance.
  • Targeting components of this pathway (Axl, Gas6, Nlrp3) or using IL-1 receptor antagonist (anakinra) or IL-18BP ameliorated morphine tolerance.

Conclusions:

  • Morphine-induced NETs are a critical factor in the development of analgesic tolerance.
  • The GAS6-AXL-TLR7/9 signaling axis represents a novel therapeutic target for overcoming morphine tolerance.
  • Interventions aimed at disrupting NETs or modulating this axis hold promise for improving pain management strategies.
Keywords:
AXLGAS6Morphine toleranceNETsNLRP3

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