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Updated: Jan 17, 2026

Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
07:23

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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Inhibition of mTOR/S6K1/Gli1 signaling alleviates morphine-induced thermal hyperalgesia and tolerance

Xing-He Wang1,2, Long Wang3, Long Yang4

  • 1Jiangsu Province Key Laboratory of Anesthesiology, Jiangsu Province Key Laboratory of Anesthesia and Analgesia Application Technology, NMPA Key Laboratory for Research and Evaluation of Narcotic and Psychotropic Drugs, Xuzhou Medical University, Jiangsu, China.

Molecular Pain
|September 19, 2025
PubMed
Abstract

Insights

The mTOR pathway and sonic hedgehog signaling are key to morphine-induced hyperalgesia and tolerance. Inhibiting these pathways, particularly mTOR/p70 ribosomal S6 protein kinase 1 (S6K1)/Gli1, reduces brain-derived neurotrophic factor (BDNF) and mitigates pain.

Area of Science:

  • Neuroscience
  • Pharmacology

Background:

  • Opioid-induced thermal hyperalgesia and tolerance mechanisms remain unclear.
  • Understanding these mechanisms is crucial for managing chronic pain and opioid dependence.

Purpose of the Study:

  • To investigate the role of the non-canonical sonic hedgehog (Shh) signaling pathway in morphine-induced thermal hyperalgesia (MITH) and tolerance.
  • To elucidate the involvement of the mTOR pathway and brain-derived neurotrophic factor (BDNF) in MITH and tolerance.

Main Methods:

  • Adult CD-1 mice received repeated morphine treatment.
  • Examined Shh signaling, behavioral changes, and neurochemical alterations in the spinal cord and DRG.
  • Utilized BDNF inhibitors and mTOR pathway modulators (activators and suppressors).

Main Results:

  • Repeated morphine induced thermal hyperalgesia and tolerance in mice.
  • Suppression of the mTOR pathway significantly inhibited MITH and tolerance.
  • Blocking mTOR/p70 ribosomal S6 protein kinase 1 (S6K1)/Gli1 signaling reduced morphine-induced BDNF increase.
  • mTOR activation caused hyperalgesia and BDNF upregulation; BDNF suppression mitigated this effect.

Conclusions:

  • The non-canonical Shh signaling pathway is implicated in MITH and tolerance.
  • This pathway mediates MITH and tolerance by regulating BDNF expression.
  • Targeting the mTOR/Shh/BDNF axis may offer therapeutic strategies for opioid-induced hyperalgesia.
Keywords:
Hedgehoghyperalgesiamammalian target of rapamycinmorphine

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