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Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice.

Publication ,  Journal Article
Liu, Y-C; Berta, T; Liu, T; Tan, P-H; Ji, R-R
Published in: Mol Pain
March 25, 2012

BACKGROUND: Despite decades of intense research efforts, actions of acute opioids are not fully understood. Increasing evidence suggests that in addition to well-documented antinociceptive effects opioids also produce paradoxical hyperalgesic and excitatory effects on neurons. However, most studies focus on the pronociceptive actions of chronic opioid exposure. Matrix metalloproteinase 9 (MMP-9) plays an important role in neuroinflammation and neuropathic pain development. We examined MMP-9 expression and localization in dorsal root ganglia (DRGs) after acute morphine treatment and, furthermore, the role of MMP-9 in modulating acute morphine-induced analgesia and hyperalgesia in mice. RESULTS: Subcutaneous morphine induced a marked up-regulation of MMP-9 protein in DRGs but not spinal cords. Morphine also increased MMP-9 activity and mRNA expression in DRGs. MMP-9 up-regulation peaked at 2 h but returned to the baseline after 24 h. In DRG tissue sections, MMP-9 is expressed in small and medium-sized neurons that co-express mu opioid receptors (MOR). In DRG cultures, MOR agonists morphine, DAMGO, and remifentanil each increased MMP-9 expression in neurons, whereas the opioid receptor antagonist naloxone and the MOR-selective antagonist D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH₂ (CTAP) suppressed morphine-induced MMP-9 expression. Notably, subcutaneous morphine-induced analgesia was enhanced and prolonged in Mmp9 knockout mice and also potentiated in wild-type mice receiving intrathecal injection of MMP-9 inhibitors. Consistently, intrathecal injection of specific siRNA targeting MMP-9 reduced MMP-9 expression in DRGs and enhanced and prolonged morphine analgesia. Subcutaneous morphine also produced heat hyperalgesia at 24 h, but this opioid-induced hyperalgesia was not enhanced after MMP-9 deletion or inhibition. CONCLUSIONS: Transient MMP-9 up-regulation in DRG neurons can mask opioid analgesia, without modulating opioid-induced hyperalgesia. Distinct molecular mechanisms (MMP-9 dependent and independent) control acute opioid-induced pronociceptive actions (anti-analgesia in the first several hours and hyperalgesia after 24 h). Targeting MMP-9 may improve acute opioid analgesia.

Duke Scholars

Published In

Mol Pain

DOI

EISSN

1744-8069

Publication Date

March 25, 2012

Volume

8

Start / End Page

19

Location

United States

Related Subject Headings

  • Sensory Receptor Cells
  • Real-Time Polymerase Chain Reaction
  • Neurology & Neurosurgery
  • Morphine
  • Mice
  • Matrix Metalloproteinase 9
  • Male
  • Interleukin-1beta
  • Immunohistochemistry
  • Blotting, Western
 

Citation

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Liu, Y.-C., Berta, T., Liu, T., Tan, P.-H., & Ji, R.-R. (2012). Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice. Mol Pain, 8, 19. https://doi.org/10.1186/1744-8069-8-19
Liu, Yen-Chin, Temugin Berta, Tong Liu, Ping-Heng Tan, and Ru-Rong Ji. “Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice.Mol Pain 8 (March 25, 2012): 19. https://doi.org/10.1186/1744-8069-8-19.
Liu, Yen-Chin, et al. “Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice.Mol Pain, vol. 8, Mar. 2012, p. 19. Pubmed, doi:10.1186/1744-8069-8-19.
Journal cover image

Published In

Mol Pain

DOI

EISSN

1744-8069

Publication Date

March 25, 2012

Volume

8

Start / End Page

19

Location

United States

Related Subject Headings

  • Sensory Receptor Cells
  • Real-Time Polymerase Chain Reaction
  • Neurology & Neurosurgery
  • Morphine
  • Mice
  • Matrix Metalloproteinase 9
  • Male
  • Interleukin-1beta
  • Immunohistochemistry
  • Blotting, Western