Morphine promotes migration and lung metastasis of mouse melanoma cells

Golnaz Vaseghi; Nasim Dana; Ahmad Ghasemi; Reza Abediny; Ismail Laher; Shaghayegh Haghjooy Javanmard

doi:10.1016/j.bjane.2021.10.019

Morphine promotes migration and lung metastasis of mouse melanoma cells

Braz J Anesthesiol. 2023 Jul-Aug;73(4):441-445. doi: 10.1016/j.bjane.2021.10.019. Epub 2022 Feb 1.

Authors

Golnaz Vaseghi¹, Nasim Dana², Ahmad Ghasemi², Reza Abediny², Ismail Laher³, Shaghayegh Haghjooy Javanmard⁴

Affiliations

¹ Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical sciences, Isfahan, Iran; Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
² Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran.
³ Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran; Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
⁴ Applied Physiology Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran. Electronic address: shaghayegh.haghjoo@gmail.com.

Abstract

Background: Morphine is an analgesic agent used for cancer pain management. There have been recent concerns that the immunosuppressant properties of morphine can also promote cancer metastasis. Morphine is an agonist for toll like receptor 4 (TLR4) that has a dual role in cancer development. The promotor or inhibitor role of morphine in cancer progression remains controversial. We investigated the effects of morphine on migration and metastasis of melanoma cells through TLR4 activation.

Methods: Mouse melanoma cells (B16F10) were treated with only morphine (0, 0.1, 1, and 10 μM) or in combination with a TLR4 inhibitor (morphine10 μM +CLI-095 1μM) for either 12 or 24 hours. Migration of cells was analyzed by transwell migration assays. Twenty C57BL/6 male mice were inoculated with B16F10 cells via the left ventricle of the heart and then randomly divided into two groups (n = 10 each) that received either morphine (10 mg.kg^-1, sub-q) or PBS injection for 21 days (control group). Animals were euthanized and their lungs removed for evaluation of metastatic nodules.

Results: Morphine (0.1, 1, and 10 μM) increased cell migration after 12 hours (p < 0.001) and after 24 hours of treatment with morphine (10 μM) (p < 0.001). Treatment with CLI-095 suppressed migration compared to cells treated with morphine alone (p < 0.001). Metastatic nodules in the morphine-treated group (64 nodules) were significantly higher than in the control group (40 nodules) (p < 0.05).

Conclusion: Morphine increases the migration and metastasis of mouse melanoma cells by activating TLR4.

Keywords: Morphine; melanoma; metastasis; toll-like receptor-4.

MeSH terms

Animals
Lung Neoplasms* / drug therapy
Lung Neoplasms* / secondary
Male
Melanoma* / pathology
Mice
Mice, Inbred C57BL
Morphine / pharmacology
Toll-Like Receptor 4

Substances

Morphine
ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate
Toll-Like Receptor 4