Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in miceReportar como inadecuado




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Molecular Pain

, 8:19

First Online: 25 March 2012Received: 28 December 2011Accepted: 25 March 2012

Abstract

BackgroundDespite 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.

ResultsSubcutaneous 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.

ConclusionsTransient 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.

KeywordsDorsal root ganglion Metalloprotease MMP-9 mu opioid receptor MOR Opioid-induced analgesia Opioid-induced hyperalgesia OIH Spinal cord Electronic supplementary materialThe online version of this article doi:10.1186-1744-8069-8-19 contains supplementary material, which is available to authorized users.

Yen-Chin Liu, Temugin Berta contributed equally to this work.

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Autor: Yen-Chin Liu - Temugin Berta - Tong Liu - Ping-Heng Tan - Ru-Rong Ji

Fuente: https://link.springer.com/







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