The Impact of OPIUM and Its Derivatives on Cell Apoptosis and Angiogenesis

Document Type : Review


1 Urology Research Centre, Tehran University of Medical Sciences, Tehran, Iran

2 Cancer Research Centre, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran

3 Paediatric urology Department, Tehran university of Medical Sciences, Tehran, Iran

4 Genomic Research Centre (GRC), Shahid Beheshti University of Medical Sciences (SBMU), Tehran, Iran



Opium is an opiate substance with a significant effect on human physiology and behavior. Ancient priests used opium as a powerful healing drug and many medical texts have referred to opium as medication, especially during the nineteenth century. In old days, the medical use of opium was popular and was called “God’s medicine”. On the other hand, understanding the molecular pathway of opium function within cells is very essential from pathophysiological views and clinical applications. The current literature shows that opium can initialize cell death through activation of apoptotic events, which in turn induces cascade pathways of angiogenesis. In this review article we attempt to investigate the effects of opium on cell apoptosis and angiogenesis.


  • Opium is an opiate substance with a significant effect on human physiology and behaviour.
  • Opium can initialize cell death through activation of apoptotic events which in turn induces cascade pathways of angiogenesis.
  • Opium and its derivates such as morphine, codeine, noscapine, and papaverine increase the rate of cellular apoptosis and angiogenesis through various mechanisms in most cells.
  • Opium and its derivates can disrupt an organ’s normal function.


1. Mohammadi A, Darabi M, Nasry M, Saabet-Jahromi M-J, Malek-Pour-Afshar R, Sheibani H. Effect of opium addiction on lipid profile and atherosclerosis formation in hypercholesterolemic rabbits. Experimental and toxicologic pathology. 2009;61(2):145-9.
2. Mohammady G, Darabi-Amin M, javad Sabet-Jahromi M, Sheibani H, Nasry M, Puor–Afshar RM. EFFECT OF OPIUM ADDICTION ON LIPID PROFILE AND ATHEROSCLEROSIS AMONG NORMAL AND HYPERCHOLESTEROLEMIC RABBITS. Journal of Diabetes and Metabolic Disorders. 2007;6:3.
3. Karam GA, Reisi M, Kaseb AA, Khaksari M, Mohammadi A, Mahmoodi M. Effects of opium addiction on some serum factors in addicts with non‐insulin‐dependent diabetes mellitus. Addiction biology. 2004;9(1):53-8.
4. Hosseini SY, Amini E, Safarinejad MR, Soleimani M, Lashay A, Farokhpey AH. Influence of opioid consumption on serum prostate-specific antigen levels in men without clinical evidence of prostate cancer. Urology. 2012;80(1):169-73.
5. Bolelli G, Lafisca S, Flamnigni C, Lodi S, Franceschetti F, Filicori M, et al. Heroin addiction: relationship between the plasma levels of testosterone, dihydrotestosterone, androstenedione, LH, FSH, and the plasma concentration of heroin. Toxicology. 1979;15(1):19-29.
6. El-Shoura S, Aziz MA, Ali M, El-Said M, Ali K, Kemeir M, et al. Andrology: Deleterious effects of khat addiction on semen parameters and sperm ultrastructure. Human Reproduction. 1995;10(9):2295-300.
7. Banerjee A, Pakrashi A, Chatterjee S, Ghosh S, Dutta S. Semen characteristics of tobacco users in India. Archives of andrology. 1993;30(1):35-40.
8. Ragni G, De LL, Gambaro V, Di RP, Bestetti O, Recalcati F, et al. Semen evaluation in heroin and methadone addicts. Acta europaea fertilitatis. 1985;16(4):245-9.
9. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. The Journal of Pain. 2002;3(5):377-84.
10. Bidlack JM. Detection and function of opioid receptors on cells from the immune system. Clin Diagn Lab Immunol. 2000;7(5):719-23.
11. Roy S, Charboneau RG, Barke RA. Morphine synergizes with lipopolysaccharide in a chronic endotoxemia model. Journal of neuroimmunology. 1999;95(1-2):107-14.
12. Mazumder DG. Effect of chronic intake of arsenic-contaminated water on liver. Toxicology and applied pharmacology. 2005;206(2):169-75.
13. Kalant H. Opium revisited: a brief review of its nature, composition, non‐medical use and relative risks 1. Addiction. 1997;92(3):267-77.
14. Hosseini SY, Safarinejad MR, Amini E, Hooshyar H, editors. Opium consumption and risk of bladder cancer: a case-control analysis. Urologic Oncology: Seminars and Original Investigations; 2010: Elsevier.
15. Mousavi MRA, Damghani MA, Haghdoust AA, Khamesipour A. Opium and risk of laryngeal cancer. The Laryngoscope. 2003;113(11):1939-43.
16. Pacifici R, di Carlo S, Bacosi A, Pichini S, Zuccaro P. Pharmacokinetics and cytokine production in heroin and morphine-treated mice. International journal of immunopharmacology. 2000;22(8):603-14.
17. Roy S, Wang J, Gupta S, Charboneau R, Loh HH, Barke RA. Chronic morphine treatment differentiates T helper cells to Th2 effector cells by modulating transcription factors GATA 3 and T-bet. Journal of neuroimmunology. 2004;147(1-2):78-81.
18. Bhat RS, Bhaskaran M, Mongia A, Hitosugi N, Singhal PC. Morphine‐induced macrophage apoptosis: oxidative stress and strategies for modulation. Journal of leukocyte biology. 2004;75(6):1131-8.
19. Weiner HL. Induction and mechanism of action of transforming growth factor‐β‐secreting Th3 regulatory cells. Immunological reviews. 2001;182(1):207-14.
20. Weiner HL. Oral tolerance: immune mechanisms and the generation of Th3-type TGF-beta-secreting regulatory cells. Microbes and infection. 2001;3(11):947-54.
21. Zheng SG, Gray JD, Ohtsuka K, Yamagiwa S, Horwitz DA. Generation ex vivo of TGF-β-producing regulatory T cells from CD4+ CD25− precursors. The Journal of Immunology. 2002;169(8):4183-9.
22. Malik AA, Radhakrishnan N, Reddy K, Smith AD, Singhal PC. Morphine-induced macrophage apoptosis modulates migration of macrophages: use of in vitro model of urinary tract infection. Journal of endourology. 2002;16(8):605-10.
23. Sheu J-R, Yeh G-C, Fang C-L, Lin C-H, Hsiao G. Morphine-potentiated agonist-induced platelet aggregation through α2-adrenoceptors in human platelets. Journal of cardiovascular pharmacology. 2002;40(5):743-50.
24. Hsiao G, Shen M-Y, Fang C-L, Chou D-S, Lin C-H, Chen T-F, et al. Morphine-potentiated platelet aggregation in in vitro and platelet plug formation in in vivo experiments. Journal of biomedical science. 2003;10(3):292-301.
25. Nabati S, Asadikaram G, Arababadi MK, Shahabinejad G, Rezaeian M, Mahmoodi M, et al. The plasma levels of the cytokines in opium-addicts and the effects of opium on the cytokines secretion by their lymphocytes. Immunology letters. 2013;152(1):42-6.
26. Asadikaram G, Igder S, Jamali Z, Shahrokhi N, Najafipour H, Shokoohi M, et al. Effects of Different Concentrations of Opium on the Secretion of Interleukin-6, Interferon-γ and Transforming Growth Factor Beta Cytokines from Jurkat Cells. Addiction & health. 2015;7(1-2):47.
27. Najafipour H, Beik A. The impact of opium consumption on blood glucose, serum lipids and blood pressure, and related mechanisms. Frontiers in physiology. 2016;7:436.
28. Joukar S, Najafipour H, Malekpour-Afshar R, Mirzaeipour F, Nasri HR. The effect of passive opium smoking on cardiovascular indices of rabbits with normal and ischemic hearts. The open cardiovascular medicine journal. 2010;4:1.
29. Lashkarizadeh MR, Garshasbi M, Shabani M, Dabiri S, Hadavi H, Manafi-Anari H. Impact of Opium Addiction on Levels of Pro-and Anti-inflammatory Cytokines after Surgery. Addiction & health. 2016;8(1):9.
30. Ciulla TA, Rosenfeld PJ. Antivascular endothelial growth factor therapy for neovascular age-related macular degeneration. Current opinion in ophthalmology. 2009;20(3):158-65.
31. Ghazavi A, Mosayebi G, Solhi H, Rafiei M, Moazzeni SM. Serum markers of inflammation and oxidative stress in chronic opium (Taryak) smokers. Immunology letters. 2013;153(1-2):22-6.
32. Ghazavi A, Solhi H, Moazzeni SM, Rafiei M, Mosayebi G. Cytokine profiles in long-term smokers of opium (Taryak). Journal of addiction medicine. 2013;7(3):200-3.
33. Elmore S. Apoptosis: a review of programmed cell death. Toxicologic pathology. 2007;35(4):495-516.
34. Asiabanha M, Asadikaram G, Rahnema A, Mahmoodi M, Hasanshahi G, Hashemi M, et al. Chronic opium treatment can differentially induce brain and liver cells apoptosis in diabetic and non-diabetic male and female rats. The Korean Journal of Physiology & Pharmacology. 2011;15(6):327-32.
35. Igder S, Asadikaram GR, Sheykholeslam F, Sayadi AR, Mahmoodi M, Arababadi MK, et al. Opium induces apoptosis in Jurkat cells. Addiction & health. 2013;5(1-2):27.
36. Zhang Y, Chen Q, Yu L-C. Morphine: a protective or destructive role in neurons? The Neuroscientist. 2008;14(6):561-70.
37. Wang JY. The capable ABL: what is its biological function? Molecular and cellular biology. 2014;34(7):1188-97.
38. Yang Z-R, Liu M, Peng X-L, Lei X-F, Zhang J-X, Dong W-G. Noscapine induces mitochondria-mediated apoptosis in human colon cancer cells in vivo and in vitro. Biochemical and biophysical research communications. 2012;421(3):627-33.
39. Hsiao P-N, Chang M-C, Cheng W-F, Chen C-A, Lin H-W, Hsieh C-Y, et al. Morphine induces apoptosis of human endothelial cells through nitric oxide and reactive oxygen species pathways. Toxicology. 2009;256(1-2):83-91.
40. Bryant L, Doyle T, Chen Z, Cuzzocrea S, Masini E, Vinci MC, et al. Spinal ceramide and neuronal apoptosis in morphine antinociceptive tolerance. Neuroscience letters. 2009;463(1):49-53.
41. Boronat MA, García‐Fuster MJ, García‐Sevilla JA. Chronic morphine induces up‐regulation of the pro‐apoptotic Fas receptor and down‐regulation of the anti‐apoptotic Bcl‐2 oncoprotein in rat brain. British journal of pharmacology. 2001;134(6):1263-70.
42. Qian L, Tan KS, Wei S-J, Wu H-M, Xu Z, Wilson B, et al. Microglia-mediated neurotoxicity is inhibited by morphine through an opioid receptor-independent reduction of NADPH oxidase activity. The Journal of Immunology. 2007;179(2):1198-209.
43. Oliveira MT, Rego AC, Morgadinho MT, Macedo TR, Oliveira CR. Toxic effects of opioid and stimulant drugs on undifferentiated PC12 cells. Annals of the New York Academy of Sciences. 2012;965:487-96.
44. Ammon‐Treiber S, Höllt V. Morphine‐induced changes of gene expression in the brain. Addiction biology. 2005;10(1):81-9.
45. Greeneltch KM, Kelly-Welch AE, Shi Y, Keegan AD. Chronic morphine treatment promotes specific Th2 cytokine production by murine T cells in vitro via a Fas/Fas ligand-dependent mechanism. The Journal of Immunology. 2005;175(8):4999-5005.
46. Mao J, Sung B, Ji R-R, Lim G. Neuronal apoptosis associated with morphine tolerance: evidence for an opioid-induced neurotoxic mechanism. Journal of Neuroscience. 2002;22(17):7650-61.
47. Skommer J, Wlodkowic D, Deptala A. Larger than life: mitochondria and the Bcl-2 family. Leukemia research. 2007;31(3):277-86.
48. Singhal PC, Kapasi AA, Reddy K, Franki N, Gibbons N, Ding G. Morphine promotes apoptosis in Jurkat cells. Journal of leukocyte biology. 1999;66(4):650-8.
49. García-Fuster M-J, Miralles A, García-Sevilla JA. Effects of opiate drugs on Fas-associated protein with death domain (FADD) and effector caspases in the rat brain: regulation by the ERK1/2 MAP kinase pathway. Neuropsychopharmacology. 2007;32(2):399.
50. Koodie L, Ramakrishnan S, Roy S. Morphine suppresses tumor angiogenesis through a HIF-1α/p38MAPK pathway. The American journal of pathology. 2010;177(2):984-97.
51. Ondrovics M, Hoelbl-Kovacic A, Fux DA. Opioids: modulators of angiogenesis in wound healing and cancer. Oncotarget. 2017;8(15):25783.
52. Bimonte S, Barbieri A, Rea D, Palma G, Luciano A, Cuomo A, et al. Morphine promotes tumor angiogenesis and increases breast cancer progression. Biomed research international. 2015;2015.