Related Experiment Video

Updated: Oct 20, 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

Published on: July 29, 2014

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Glial IL-33 signaling through an ST2-to-CXCL12 pathway in the spinal cord contributes to morphine-induced

Xue-Ming Hu1, Wei Yang1, Meng-Ting Zhang1,2

  • 1Department of Integrative Medicine and Neurobiology, School of Basic Medical Science, Institutes of Integrative Medicine, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Institutes of Brain Science, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Science Signaling
|September 13, 2021
PubMed

Insights

Targeting interleukin-33 (IL-33) and its receptor ST2 in the spinal cord can prevent opioid-induced hyperalgesia and tolerance, offering a new strategy for effective chronic pain management.

Area of Science:

  • Neuroscience
  • Immunology
  • Pharmacology

Background:

  • Opioids like morphine are effective for severe pain but can cause hyperalgesia and tolerance, limiting long-term use.
  • The molecular mechanisms behind morphine-induced hyperalgesia and tolerance are not fully understood.
  • Interleukin-33 (IL-33) and its receptor ST2 are implicated in inflammatory and pain pathways.

Purpose of the Study:

  • To investigate the role of interleukin-33 (IL-33) and its receptor ST2 in morphine-induced hyperalgesia and analgesic tolerance.
  • To elucidate the molecular pathways involved in IL-33/ST2-mediated opioid side effects.

Main Methods:

  • Repeated subcutaneous morphine injections in mice.
  • Measurement of IL-33 and ST2 expression in the spinal cord.
  • Pharmacological inhibition and genetic knockdown/knockout of IL-33 and ST2.
  • Assessment of astroglial activation, synaptic transmission, and pain behaviors.
  • Analysis of the TRAF6-JNK-CXCL12 pathway.

Main Results:

  • Morphine treatment increased IL-33 and ST2 abundance in spinal cord astrocytes and oligodendrocytes.
  • Inhibition or genetic deletion of IL-33 or ST2 attenuated morphine-induced hyperalgesia and tolerance.
  • IL-33/ST2 signaling promoted astroglial activation and enhanced excitatory synaptic transmission.
  • A pathway involving TRAF6, JNK, and CXCL12 in astrocytes mediated IL-33's effects.

Conclusions:

  • Spinal IL-33/ST2 signaling is a key mediator of morphine-induced hyperalgesia and analgesic tolerance.
  • Targeting the IL-33-ST2 pathway, potentially via TRAF6 and CXCL12, offers a promising strategy for sustained opioid analgesia in chronic pain.
  • This research opens new avenues for managing chronic pain by enhancing the efficacy and durability of opioid treatments.

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