Title |
Acute Morphine Induces Matrix Metalloproteinase-9 Up-Regulation in Primary Sensory Neurons to Mask Opioid-Induced Analgesia in Mice
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Published in |
Molecular Pain, January 2012
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DOI | 10.1186/1744-8069-8-19 |
Pubmed ID | |
Authors |
Yen-Chin Liu, Temugin Berta, Tong Liu, Ping-Heng Tan, Ru-Rong Ji |
Abstract |
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. 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-NHâ‚‚ (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. 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. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 53 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 13 | 25% |
Student > Ph. D. Student | 9 | 17% |
Professor | 4 | 8% |
Student > Master | 4 | 8% |
Student > Bachelor | 2 | 4% |
Other | 9 | 17% |
Unknown | 12 | 23% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 17 | 32% |
Medicine and Dentistry | 11 | 21% |
Neuroscience | 8 | 15% |
Pharmacology, Toxicology and Pharmaceutical Science | 2 | 4% |
Biochemistry, Genetics and Molecular Biology | 2 | 4% |
Other | 1 | 2% |
Unknown | 12 | 23% |