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Morphine and other opioids are used to manage cancer-related pain; however, the role of these drugs in cancer progression remains controversial. Emerging evidence indicates that morphine can activate Toll-like receptor 4 (TLR4) and its signaling pathways, by the way the activation and expression of TLR4 can promote melanoma. In this study, we investigated the effects of morphine on the expression of TLR4 and promotion of melanoma in mice. Mice melanoma cells (B16F10) were cultured with morphine (0.1, 1 and 10 µM) for 24 h. In the other experiment, cells were treated with morphine with or without TLR4 agonist (LPS) or antagonist (TAK-242). In  in-vivo  model, B16F10 cells were subcutaneously injected to C57BL/6 mice, and morphine was administrated in three different treatment protocols after developing palpable tumors (acute treatment, chronic daily injections, escalating doses of morphine). In another set of experiments, B16F10 cells were pretreated with LPS (5 µg/ml) 24 h before injection into mice. Control group received normal saline. We measured cell proliferation, the expression level of  Tlr4 , Nuclear factor kappa-light-chain-enhancer of activated B cells 1 ( Nf-κb1 ) genes, TLR4 protein expression, and tumor volume. Chronic, acute, and escalating doses of morphine increased tumor. Morphine increased the expression of  Tlr4  and  Nf-κb1  regardless of the treatment protocol used. Morphine increases the progression of melanoma cancer and may be related to the increased expression of TLR4. Our results suggest that morphine should be used with caution in patients with melanoma.HighlightsMorphine increases the expression of TLR4 in melanoma.Morphine increases melanoma progression.These effects are mostly observed with chronic and escalating morphine administration Morphine increases the expression of TLR4 in melanoma. Morphine increases melanoma progression. These effects are mostly observed with chronic and escalating morphine administration

Morphine upregulates Toll-like receptor 4 expression and promotes melanomas in mice