Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways

Toxicology. 2009 Feb 4;256(1-2):83-91. doi: 10.1016/j.tox.2008.11.015. Epub 2008 Nov 25.


Morphine has been widely used for pain management. Other than analgesia, it has effects on vascular endothelial cells, including angiogenesis and apoptosis. An in vitro model of human umbilical vein endothelial cells (HUVECs) was made to investigate the effects and comprehensive mechanisms of morphine on vascular endothelial cells. Morphine enhanced apoptosis of HUVECs, increased intracellular reactive oxygen species (ROS), and reduced mitochondrial membrane potentials (MMPs). It also induced the release of NO and activated NF-kappaB in HUVECs. Naloxone, the opioid receptor antagonist, could reverse cell apoptosis and ROS generation, NO production, and MMP loss. Expression levels of Bak and Bax, and the activation of caspases 3 and 7 in HUVECs significantly increased when treated with morphine. Inhibition of NO production by NO synthase inhibitor reduced morphine-induced apoptosis. Morphine could induce apoptosis of HUVECs through both the NO and ROS pathways. Thus, inhibiting NO or ROS may be a potential target in blocking morphine-induced apoptosis of endothelial cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology*
  • Apoptosis / drug effects*
  • Blotting, Western
  • Caspase 3 / metabolism
  • Caspase 7 / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Endothelial Cells / drug effects*
  • Flow Cytometry
  • Humans
  • Hydrogen Peroxide / analysis
  • Hydrogen Peroxide / metabolism
  • Immunoprecipitation
  • Membrane Potentials / drug effects
  • Mitochondrial Membranes / drug effects
  • Morphine / pharmacology*
  • NF-kappa B / metabolism
  • Nitric Oxide / physiology*
  • Reactive Oxygen Species / metabolism*


  • Analgesics, Opioid
  • NF-kappa B
  • Reactive Oxygen Species
  • Nitric Oxide
  • Morphine
  • Hydrogen Peroxide
  • Caspase 3
  • Caspase 7