Chronic morphine treatment inhibits LPS-induced angiogenesis: implications in wound healing.
Delayed wound healing is a chronic problem in opioid drug abusers. We investigated the role chronic morphine plays on later stages of wound healing events using an angiogenesis model. Our results show that morphine treatment resulted in a significant decrease in inflammation induced angiogenesis. To delineate the mechanisms involved we investigate the role of hypoxia inducible factor 1 alpha (HIF-1 alpha), a potent inducer of angiogenic growth factor. Morphine treatment resulted in a significant decrease in the expression and nuclear translocation of HIF-1 alpha with a concurrent suppression in vascular endothelial growth factor (VEGF) synthesis. Cells of the innate immune system play a dominant role in the angiogenic process. Morphine treatment inhibited early recruitment of both neutrophils and monocytes towards an inflammatory signal with a significant decrease in the monocyte chemoattractant MCP-1. Taken together, our studies show that morphine regulates the wound repair process on multiple levels. Morphine acts both directly and indirectly in suppressing angiogenesis.
Martin
Josephine L
JL
Department of Pharmacology, University of Minnesota, 6-120 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455, USA.
Charboneau
Richard
R
Barke
Roderick A
RA
Roy
Sabita
S
D043925:Angiogenesis Inducing Agents / Q000494:pharmacology; D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects; D018932:Chemokine CCL2 / Q000378:metabolism; D004336:Drug Antagonism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D009000:Monocytes / Q000378:metabolism; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000188:drug therapy*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
D043925:Angiogenesis Inducing Agents; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008070:Lipopolysaccharides; D042461:Vascular Endothelial Growth Factor A; D009020:Morphine