title: Acute morphine induces matrix metalloproteinase-9 up-regulation in primary sensory neurons to mask opioid-induced analgesia in mice.
abstract: 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.
authors.affiliation: Sensory Plasticity Laboratory, Pain Research Center, Department of Anesthesiology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Yen-Chin
authors.initials: YC
authors.lastname: Liu
authors.forename: Temugin
authors.initials: T
authors.lastname: Berta
authors.forename: Tong
authors.initials: T
authors.lastname: Liu
authors.forename: Ping-Heng
authors.initials: PH
authors.lastname: Tan
authors.forename: Ru-Rong
authors.initials: RR
authors.lastname: Ji
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D015153:Blotting, Western; D007150:Immunohistochemistry; D053583:Interleukin-1beta / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009020:Morphine / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D011984:Sensory Receptor Cells / Q000187:drug effects* / Q000201:enzymology*
chemical_list: D000701:Analgesics, Opioid; D053583:Interleukin-1beta; D009020:Morphine; D020780:Matrix Metalloproteinase 9