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Updated: May 13, 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

Microglia activation precedes the anti-opioid BDNF and NMDA receptor mechanisms underlying morphine analgesic

Yosuke Matsushita, Idowu O Omotuyi, Takehiro Mukae

  • 1Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, 1-14 Bunkyo-machi, Nagasaki 852-8521, Japan. ueda@nagasaki-u.ac.jp.

Current Pharmaceutical Design
|March 2, 2013
PubMed

Insights

Microglia activation in the periaqueductal gray (PAG) drives morphine tolerance through brain-derived neurotrophic factor (BDNF) release and NMDA receptor expression. Inhibiting microglia reverses this opioid tolerance.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Cell Biology

Background:

  • Morphine tolerance, a significant clinical challenge, limits long-term opioid therapy effectiveness.
  • The role of microglia, the brain's resident immune cells, in opioid tolerance remains incompletely understood.
  • The periaqueductal gray (PAG) is a critical brain region involved in pain modulation and opioid action.

Purpose of the Study:

  • To investigate the involvement of periaqueductal gray (PAG)-resident microglia in the development of morphine tolerance.
  • To elucidate the underlying molecular mechanisms, including the roles of brain-derived neurotrophic factor (BDNF) and NMDA receptors.

Main Methods:

  • Utilized microglia inhibitors (clodronate, minocycline) to assess their impact on morphine tolerance.
  • Employed conditional BDNF knockout mice (BDNF⁻/⁻) to examine the necessity of BDNF signaling.
  • Investigated the expression levels of BDNF and NMDA receptor subunits (NR2A) following chronic morphine treatment and pharmacological interventions.

Main Results:

  • Microglia inhibition reversed established morphine tolerance, confirming microglia activation's crucial role.
  • Conditional knockout of BDNF prevented the development of morphine tolerance.
  • Microglia activation led to increased BDNF expression, which in turn upregulated NMDA receptor subunit NR2A, demonstrating a sequential mechanism.

Conclusions:

  • Microglia activation in the PAG is a key driver of morphine tolerance.
  • The microglia-mediated pathway involves sequential release of BDNF and subsequent upregulation of NMDA receptor expression.
  • Targeting microglia and the BDNF-glutamatergic pathway presents a potential therapeutic strategy for managing opioid tolerance.

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