Brazilian Journal of Anesthesiology
Brazilian Journal of Anesthesiology
Original Investigation

Morphine promotes migration and lung metastasis of mouse melanoma cells

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

Downloads: 0
Views: 26


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.

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 (10−1, sub-q) or PBS injection for 21 days (control group). Animals were euthanized and their lungs removed for evaluation of metastatic nodules.

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).

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


Morphine;  toll-like receptor-4;  melanoma;  metastasis


1 Z Li, T Aninditha, B Griene, et al. Burden of cancer pain in developing countries: a narrative literature review Clinicoecon Outcomes Res: CEOR, 10 (2018), pp. 675-691

2 RA Swarm, AP Abernethy, DL Anghelescu, et al. Adult cancer pain J Natl Compr Canc Netw: JNCCN, 11 (2013), pp. 992-1022

3 B Afsharimani, J Baran, S Watanabe, et al. Morphine and breast tumor metastasis: the role of matrix-degrading enzymes Clin Exp Metastasis, 31 (2014), pp. 149-158

4 R Vallejo, O de Leon-Casasola, R. Benyamin Opioid therapy and immunosuppression: a review Am J Ther, 11 (2004), pp. 354-365

5 A Ghasemi, G Vaseghi, A Hojjatallah, et al. The effects of morphine on vascular cell adhesion molecule 1(VCAM-1) concentration in lung cancer cells Arch Physiol Biochem (2021), 10.1080/13813455.2020.1838552 [Ahead of print]

6 I Tegeder, S Grösch, A Schmidtko, et al. G protein-independent G1 cell cycle block and apoptosis with morphine in adenocarcinoma cells: involvement of p53 phosphorylation Cancer Res, 63 (2003), pp. 1846-1852

7 T Sasamura, S Nakamura, Y Iida, et al. Morphine analgesia suppresses tumor growth and metastasis in a mouse model of cancer pain produced by orthotopic tumor inoculation Eur J Pharmacol, 441 (2002), pp. 185-191

8 Y Harimaya, K Koizumi, T Andoh, et al. Potential ability of morphine to inhibit the adhesion, invasion and metastasis of metastatic colon 26-L5 carcinoma cells Cancer Lett, 187 (2002), pp. 121-127

9 FE Lennon, T Mirzapoiazova, B Mambetsariev, et al. The Mu opioid receptor promotes opioid and growth factor-induced proliferation, migration and Epithelial Mesenchymal Transition (EMT) in human lung cancer PloS one, 9 (2014), p. e91577

10 P Ecimovic, D Murray, P Doran, et al. Direct effect of morphine on breast cancer cell function in vitro: role of the NET1 gene Br J Anaesth, 107 (2011), pp. 916-923

11 M Farooqui, Y Li, T Rogers, et al. COX-2 inhibitor celecoxib prevents chronic morphine-induced promotion of angiogenesis, tumour growth, metastasis and mortality, without compromising analgesia Br J Cancer, 97 (2007), pp. 1523-1531

12 R Maneckjee, R Biswas, BK. Vonderhaar Binding of opioids to human MCF-7 breast cancer cells and their effects on growth Cancer Res, 50 (1990), pp. 2234-2238

13 S Bimonte, A Barbieri, G Palma, et al. The role of morphine in animal models of human cancer: does morphine promote or inhibit the tumor growth? Biomed Res Int, 2013 (2013), Article 258141

14 M Ishikawa, K Tanno, A Kamo, et al. Enhancement of tumor growth by morphine and its possible mechanism in mice Biol Pharm Bull, 16 (1993), pp. 762-766

15 XY Zhang, YX Liang, Y Yan, et al. Morphine: double-faced roles in the regulation of tumor development Clin Transl Oncol, 20 (2018), pp. 808-814

16 T Kaserer, A Lantero, H Schmidhammer, et al. μ Opioid receptor: novel antagonists and structural modeling Sci Rep, 6 (2016), p. 21548

17 G Vaseghi, M Rabbani, V. Hajhashemi The effect of nimodipine on memory impairment during spontaneous morphine withdrawal in mice: Corticosterone interaction Eur J Pharmacol, 695 (2012), pp. 83-87

18 G Vaseghi, M Rabbani, V. Hajhashemi The CB(1) receptor antagonist, AM281, improves recognition loss induced by naloxone in morphine withdrawal mice Basic Clin Pharmacol Toxicol, 111 (2012), pp. 161-165

19 P Zhang, M Yang, C Chen, et al. Toll-like receptor 4 (TLR4)/opioid receptor pathway crosstalk and impact on opioid analgesia, immune function, and gastrointestinal motility Front Immunol, 11 (2020), p. 1455

20 C Vaure, Y. Liu A comparative review of toll-like receptor 4 expression and functionality in different animal species Front Immunol, 5 (2014), p. 316

21 Y Sato, Y Goto, N Narita, et al. Cancer cells expressing toll-like receptors and the tumor microenvironment Cancer Microenviron, 2 (S1) (2009), pp. 205-214

22 N Xie, N Matigian, T Vithanage, et al. Effect of perioperative opioids on cancer-relevant circulating parameters: mu opioid receptor and toll-like receptor 4 activation potential, and proteolytic profile Clin Cancer Res, 24 (2018), pp. 2319-2327

23 N Xie, FP Gomes, V Deora, et al. Activation of μ-opioid receptor and Toll-like receptor 4 by plasma from morphine-treated mice Brain Behav Immun, 61 (2017), pp. 244-258

24 J Li, F Yang, F Wei, et al. The role of toll-like receptor 4 in tumor microenvironment Oncotarget, 8 (2017), pp. 66656-66667

25 H Yang, B Wang, T Wang, et al. Toll-Like Receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis Dileepan KN, editor. PLoS ONE, 9 (2014), Article e109980

26 EL Wang, ZR Qian, M Nakasono, et al. High expression of Toll-like receptor 4/myeloid differentiation factor 88 signals correlates with poor prognosis in colorectal cancer Br J Cancer, 102 (2010), pp. 908-915

27 N Dana, SH Javanmard, G. Vaseghi Effect of lipopolysaccharide on toll-like receptor-4 signals in mouse cancer cells Bratislavske Lekarske Listy, 118 (2017), pp. 598-601

28 N Dana, Javanmard S Haghjooy, G Vaseghi The effect of fenofibrate, a PPARα activator on toll-like receptor-4 signal transduction in melanoma both in vitro and in vivo Clin Transl Oncol, 22 (2020), pp. 486-494

29 N Dana, G Vaseghi, Javanmard S Haghjooy PPAR γ agonist, pioglitazone, suppresses melanoma cancer in mice by inhibiting TLR4 signaling J Pharm Pharm Sci, 22 (2019), pp. 418-423

30 S Haghjooy-Javanmard, A Ghasemi, I Laher, et al. Influence of morphine on TLR4/NF-kB signaling pathway of MCF-7 cells Bratisl Lek Listy, 119 (2018), pp. 229-233

31 C Venter, C. Niesler Rapid quantification of cellular proliferation and migration using ImageJ BioTechniques, 66 (2019), pp. 99-102

32 L-H Cao, H-T Li, W-Q Lin, et al. Morphine, a potential antagonist of cisplatin cytotoxicity, inhibits cisplatin-induced apoptosis and suppression of tumor growth in nasopharyngeal carcinoma xenografts Sci Rep, 6 (2016), p. 18706

33 B Zbytek, JA Carlson, J Granese, et al. Current concepts of metastasis in melanoma Expert Rev Dermatol, 3 (2008), pp. 569-585

34 JE Talmadge, IJ. Fidler AACR centennial series: the biology of cancer metastasis: historical perspective Cancer Res, 70 (2010), pp. 5649-5669

35 G Vaseghi, S Haghjoo-Javanmard, J Naderi, et al. Coffee consumption and risk of nonmelanoma skin cancer: a dose–response meta-analysis Eur J Cancer Prev, 27 (2018), pp. 164-170

36 N Dana, G Vaseghi, Javanmard S Haghjooy Activation of PPARγ inhibits TLR4 signal transduction pathway in melanoma cancer in vitro Adv Pharm Bull, 10 (2020), pp. 458-463

37 N Dana, G Vaseghi, S. Haghjooy-Javanmard Crosstalk between peroxisome proliferator-activated receptors and toll-like receptors: a systematic review Adv Pharm Bull, 9 (2019), pp. 12-21

38 D Mittal, F Saccheri, E Vénéreau, et al. TLR4-mediated skin carcinogenesis is dependent on immune and radioresistant cells EMBO J, 29 (2010), pp. 2242-2252

39 X Liang, R Liu, C Chen, et al. Opioid system modulates the immune function: a review Transl Perioper Pain Med, 1 (2016), pp. 5-13

40 X Wang, LC Loram, K Ramos, et al. Morphine activates neuroinflammation in a manner parallel to endotoxin Proc Natl Acad Sci U S A, 109 (2012), pp. 6325-6330

41 K Gach, J Szemraj, A Wyrębska, et al. The influence of opioids on matrix metalloproteinase-2 and -9 secretion and mRNA levels in MCF-7 breast cancer cell line Mol Biol Rep, 38 (2011), pp. 1231-1236

42 H Tuerxun, J. Cui The dual effect of morphine on tumor development Clin Transl Oncol, 21 (2019), pp. 695-701

43 K Gupta, S Kshirsagar, L Chang, et al. Morphine stimulates angiogenesis by activating proangiogenic and survival-promoting signaling and promotes breast tumor growth Cancer Res, 62 (2002), pp. 4491-4498

44 S Cheng, M Guo, Z Liu, et al. Morphine promotes the angiogenesis of postoperative recurrent tumors and metastasis of dormant breast cancer cells Pharmacology, 104 (2019), pp. 276-286

45 J Zong, GM. Pollack Morphine antinociception is enhanced in mdr1a gene-deficient mice Pharm Res, 17 (2000), pp. 749-753

626fe41da953951aea04d162 rba Articles
Links & Downloads

Braz J Anesthesiol

Share this page
Page Sections