Prolonged use of high-dose morphine impairs angiogenesis and mobilization of endothelial progenitor cells in mice.
BACKGROUND
Morphine is one of the most commonly prescribed analgesics for treating wound pain. Using a mouse model of excisional wound injury, we determined the effects of high-dose morphine on angiogenesis and mobilization of endothelial progenitor cells.


METHODS
An excisional wound was created on mice treated with placebo or morphine (20 mg/kg, i.p. injection for 14 days). Wound healing was compared by measuring the final-to-initial wound area ratio. Generation of superoxide anions in the wound was determined by luminol-enhanced chemiluminescence. Circulating mononuclear cells were isolated and measured for endothelial progenitor cell (defined as CD34+/CD133+ cell) counts. In vivo and in vitro measurements of angiogenesis after morphine treatment were performed using the Matrigel assay.


RESULTS
Mice treated with morphine had reduced wound closure and higher wound superoxide ions concentrations than control mice. Morphine reduced the number of postwound circulating endothelial progenitor cells. Matrigel assay showed impaired angiogenesis in animals and reduced capillary tube formation in cultured endothelial cells treated with morphine.


CONCLUSIONS
High-dose morphine impaired angiogenesis, increased systemic oxidative stress, and impaired mobilization of endothelial progenitor cells. This study emphasizes the potential detrimental effect of high-dose morphine on angiogenesis after systemic administration.
Lam
Chen-Fuh
CF
Department of Anesthesiology, National Cheng Kung University, Medical College and Hospital, Tainan City, Taiwan.
Chang
Pei-Jung
PJ
Huang
Yu-Sheng
YS
Sung
Yen-Hui
YH
Huang
Chien-Chi
CC
Lin
Ming-Wei
MW
Liu
Yen-Chin
YC
Tsai
Yu-Chuan
YC
D000071916:AC133 Antigen; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000032:analysis; D002465:Cell Movement / Q000187:drug effects; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000502:physiology*; D004730:Endothelium, Vascular / Q000502:physiology; D006023:Glycoproteins / Q000032:analysis; D066298:In Vitro Techniques; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008163:Luminescent Measurements; D051379:Mice; D008810:Mice, Inbred C57BL; D009020:Morphine / Q000008:administration & dosage / Q000494:pharmacology*; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D010455:Peptides / Q000032:analysis; D012867:Skin / Q000293:injuries; D013234:Stem Cells / Q000502:physiology; D013481:Superoxides / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
D000071916:AC133 Antigen; D000701:Analgesics, Opioid; D015703:Antigens, CD; D018952:Antigens, CD34; D006023:Glycoproteins; D010455:Peptides; C000606024:Prom1 protein, mouse; D013481:Superoxides; D009020:Morphine