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Updated: Dec 5, 2025

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Spinal TLR4/P2X7 Receptor-Dependent NLRP3 Inflammasome Activation Contributes to the Development of Tolerance to

Haiyan Wang1, Yu Zhang1, Xiaqing Ma1

  • 1Department of Anesthesiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, People's Republic of China.

Journal of Inflammation Research
|October 16, 2020
PubMed
Abstract

Insights

Morphine tolerance is linked to spinal cord neuroinflammation involving the NLRP3 inflammasome. Targeting Toll-like receptor 4 (TLR4) and P2X7 receptor (P2X7R) pathways may offer new treatments for morphine tolerance.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Immunology

Background:

  • Long-term morphine use causes antinociceptive tolerance, limiting its clinical use.
  • Spinal neuroinflammation, particularly involving microglia, is implicated in morphine tolerance.
  • The Nod-like receptor protein 3 (NLRP3) inflammasome is a key mediator of neuroinflammation.

Purpose of the Study:

  • To investigate the mechanisms of NLRP3 inflammasome activation in morphine-induced tolerance.
  • To elucidate the roles of Toll-like receptor 4 (TLR4) and P2X7 receptor (P2X7R) in this process.

Main Methods:

  • Established morphine tolerance in mice via intrathecal injection.
  • Utilized NLRP3 and TLR4 knockout mice, and a P2X7R antagonist (A438079).
  • Assessed antinociception using the tail-flick test; analyzed protein expression via Western blot and immunofluorescence.

Main Results:

  • Repeated morphine increased spinal NLRP3 expression and microglial activation.
  • NLRP3 knockout attenuated morphine tolerance and microglial activation.
  • TLR4 knockout and P2X7R inhibition prevented morphine tolerance and NLRP3 upregulation.
  • NLRP3, TLR4, and P2X7R were colocalized with the microglia marker Iba1.

Conclusions:

  • The NLRP3 inflammasome in microglia is critical for morphine tolerance.
  • Both TLR4- and P2X7R-dependent pathways are essential for NLRP3 inflammasome activation during morphine tolerance.
  • These findings offer a novel perspective for therapeutic strategies against morphine tolerance.
Keywords:
NLRP3P2X7RTLR4morphineneuroinflammationtolerance

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