Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice.
Tumor cells secrete factors that stimulate the migration of peripheral blood leukocytes and enhance tumor progression by affecting angiogenesis. In these studies, we investigated the effect of morphine, a known immunosuppressant, on leukocyte migration and recruitment to conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells. Our results indicate that morphine treatment reduced the migration and recruitment of tumor-infiltrating leukocytes into Matrigel plugs and polyvinyl alcohol sponges containing conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells when compared with placebo. A reciprocal increase in peripheral blood leukocytes was observed at the time of plug or sponge removal in morphine-treated mice. Decreased angiogenesis was observed in conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells Matrigel plugs taken from morphine-treated wild-type mice when compared with placebo but was abolished in morphine-treated μ-opioid receptor knockout mice. In addition, in vitro studies using trans-well and electric cell substrate impedance sensing system studies reveal for the first time morphine's inhibitory effects on leukocyte migration and their ability to transmigrate across an activated endothelial monolayer. Taken together, these studies indicate that morphine treatment can potentially decrease leukocyte transendothelial migration and reduce angiogenesis associated with tumor growth. The use of morphine for cancer pain management may be beneficial through its effects on angiogenesis.
Department of Pharmacology, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; Department of Dentistry, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; Division of Basic Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
Lisa
L
Koodie
Division of Basic Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
Hongyan
H
Yuan
Department of Dentistry, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
Jeffery A
JA
Pumper
Division of Basic Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
Haidong
H
Yu
Veterans Affairs Medical Hospital, Minneapolis, Minnesota.
Richard
R
Charboneau
Department of Dentistry, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.
Sundaram
S
Ramkrishnan
Department of Pharmacology, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; Department of Dentistry, Department of Surgery, University of Minnesota, Minneapolis, Minnesota; Division of Basic Translational Research, Department of Surgery, University of Minnesota, Minneapolis, Minnesota. Electronic address: royxx002@umn.edu.
Sabita
S
Roy
D000818:Animals; D018827:Carcinoma, Lewis Lung / Q000473:pathology*; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009020:Morphine / Q000494:pharmacology*; D009389:Neovascularization, Pathologic / Q000473:pathology*; D017450:Receptors, Opioid, mu / Q000172:deficiency / Q000235:genetics; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects*
D017077:Culture Media, Conditioned; D007166:Immunosuppressive Agents; D017450:Receptors, Opioid, mu; D009020:Morphine