Morphine Promotes Breast Cancer Cell Proliferation via μ-Opioid Receptor Independent-MRG Dependent Signaling: An in vitro Study

Systemic morphine results in significant pain relief in patients who are in advanced stage of cancer. However, the possibility that morphine may facilitate tumor development is a recent concern. Pre-clinical studies have shown that morphine may enhance tumor angiogenesis and promote cancer growth, reducing long term survival with few contradictory studies. The present study addresses the effects of morphine on cell proliferation using a rat mammary adenocarcinoma cell line (MTLn3). MTLn3 cells were cultured in MEM-alpha growth media supplemented with 5% heat-inactivated fetal bovine serum and 0.5% penstrep. Cells were incubated at 37Ë? C in a humidified 5% CO₂ environment and grown to 70%-90% confluence. To assess proliferation, MTLn3 cells were seeded (8 x 10⁴ cells/well) in a 12-well plate and incubated for 24 hours, followed by 48 hours incubation with four mu opioid agonists (morphine: 3 nM-30 M; fentanyl: 0.03 pM-0.3 TMD; M-DALDA: 3 nM-30 Pro M ZM 21: 3 nM-30 M). To examine antagonism Morphine+naloxone (3 nM-30 M), cell proliferation assays were performed after 48 hours by counting total number of cells. Morphine enhanced proliferation of MTLn3 cells following 48 hours incubation with a peak effect observed with 0.03 μM morphine. This effect was not reversed by naloxone or naltrindole. Of note, fentanyl PZM-21 nor DMTDALDA had no effect upon proliferation. The common feature is that morphine is a mu agonist that activates in a naloxone independent fashion Mas Related G-coupled (MRG) orphan receptors. The three agents not affecting cancer cell growth are potent mu agonists, but they are not considered to activate MRGs. Of note MTLn3 cells express MRGs. These results show that morphine enhanced proliferation of breast cancer cells and that the tumor enhancing effects, independent of u-opioid receptor, may reflect an effect of MRG signaling in this syngenic cell line.

Author(s): Tony L Yaksh*, Tsutomu Mieda, Roshni Ramachandran, Yuelian Zhu, Yajun He, Patrick W Mantyh and Linda M Page

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