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Assessment of Morphine-induced Hyperalgesia and Analgesic Tolerance in Mice Using Thermal and Mechanical Nociceptive Modalities
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Involvement of matrix metalloproteinase-9 in the development of morphine tolerance

Kazuo Nakamoto1, Shintaro Kawasaki, Takuro Kobori

  • 1Department of Clinical Pharmacy, Kobe Gakuin University, School of Pharmaceutical Sciences, 1-1-3 Minatojima, Chuo-ku, Kobe, Hyogo 650-8586, Japan.

European Journal of Pharmacology
|March 27, 2012
PubMed

Insights

Matrix metalloproteinase-9 (MMP-9) activation in the midbrain, not the spinal cord, contributes to morphine tolerance. Inhibiting MMP-9 partially blocks tolerance development after repeated morphine use.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Biochemistry

Background:

  • Matrix metalloproteinase-9 (MMP-9) plays a role in tissue remodeling and neural plasticity.
  • MMP-9 is implicated in various clinical conditions, including inflammation and neuropathic pain.

Purpose of the Study:

  • To investigate the role of MMP-9 in the development of morphine tolerance.
  • To determine the specific location (midbrain vs. spinal cord) of MMP-9 involvement in morphine tolerance.

Main Methods:

  • Morphine tolerance was induced in mice via daily subcutaneous injections for 5 days.
  • Antinociceptive effects were assessed using the tail flick method.
  • Mice were treated with non-specific MMP inhibitor (GM6001) or a specific MMP-9 inhibitor.
  • MMP-9 knockout mice were used for comparison.
  • MMP-9 protein expression and activity were analyzed in the midbrain and spinal cord using Western blot and gelatin zymography.

Main Results:

  • Daily treatment with GM6001 significantly inhibited morphine tolerance development.
  • A specific MMP-9 inhibitor partially inhibited tolerance when administered systemically (intracerebroventricularly), but not intrathecally.
  • Mice lacking MMP-9 exhibited partially inhibited morphine tolerance compared to wild-type.
  • MMP-9 protein levels transiently increased in the midbrain early in morphine treatment, while MMP-9 activity showed a persistent increase in the midbrain.
  • MMP-9 levels and activity remained unchanged in the spinal cord.

Conclusions:

  • Persistent MMP-9 activation in the midbrain, following an initial transient increase in expression, appears to contribute to the development of morphine tolerance.
  • The spinal cord is not the primary site for MMP-9's role in morphine tolerance.
  • Targeting MMP-9 may offer a strategy to manage morphine tolerance.

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