Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 2, pp 123–133 | Cite as

Opioids and matrix metalloproteinases: the influence of morphine on MMP-9 production and cancer progression

  • Samira Khabbazi
  • Mohammadhossein Hassanshahi
  • Alireza Hassanshahi
  • Yaser Peymanfar
  • Yu-Wen Su
  • Cory J. XianEmail author


Opioids are widely administered to alleviate pain, including chronic pain in advanced cancer patients. Among opioids, morphine is one of the most clinically effective drugs for the palliative management of severe pain. In the last few decades, there has been a debate around the possible influence of opioids such as morphine on tumour growth and metastasis. Whilst several in vitro and in vivo studies suggest the possible modulatory effects of morphine on tumour cells, little is known about the impact of this analgesic drug on other mediators such as matrix metalloproteinases (MMPs) that play a key role in the control of cancer cell invasion and metastasis. MMP-9 has been considered as one of the principal mediators in regulation of not only the initial steps of cancer but during the invasion and spreading of cancer cells to distant organs. Herein, current studies regarding the direct and indirect effects of morphine on regulation of MMP-9 production are discussed. In addition, drawing from previous in vivo and in vitro studies on morphine action in regulating MMP-9 production, the potential roles of several underlying factors are summarised, including nuclear factor kappa-B and intracellular molecules such as nitric oxide.


Opioids Matrix metalloproteinases MMP-9 Morphine NF-κB Nitric oxide 



Adenylyl cyclase


Activator protein 1


Bone marrow-derived macrophages


cAMP responsive element binding


Cyclic adenosine monophosphate


Cyclic guanosine monophosphate


Constitutive nitric oxide synthase


Dorsal root ganglia


Endothelial nitric oxide synthase


Extracellular matrix


G protein-coupled receptor


G beta-gamma


Inducible nitric oxide synthase


Interleukin 1 beta


Interleukin 4


Interleukin 6


Nuclear factor-κB inhibitor




Matrix metalloproteinases


Matrix metalloproteinase 9


Nuclear factor kappa B


Nitric oxide


Nitric oxide synthase


Neuronal nitric oxide synthase


Protein kinase C-delta


Protein kinase A


Phospholipase C


Protein kinase C


Phosphoinositide 3-kinase


Protein kinase B


Polyoma enhancer activator 3


Stimulating protein-1


Tumour necrosis factor receptor-associated factor 6


Toll-like receptor


Tissue inhibitor of metalloproteinase 1


Tumour necrosis factor alpha


Authors’ contribution

SK and MH designed and conducted the literature review and drafted the manuscript. AH, PY and YS conducted the literature review. CJX designed and conceptualised the manuscript.

Funding information

Authors’ own work discussed was supported in part by National Health and Medical Research Council Australia (NHMRC) project grants and fellowships (numbers 0508046, 0508047 and 1042105).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Samira Khabbazi
    • 1
  • Mohammadhossein Hassanshahi
    • 2
  • Alireza Hassanshahi
    • 3
  • Yaser Peymanfar
    • 2
  • Yu-Wen Su
    • 2
  • Cory J. Xian
    • 2
    Email author
  1. 1.School of Medical Science, The South Australian Health and Medical Research InstituteThe University of AdelaideAdelaideAustralia
  2. 2.School of Pharmacy and Medical Sciences, and University of South Australia Cancer Research InstituteUniversity of South AustraliaAdelaideAustralia
  3. 3.Department of Genetics, Faculty of Basic SciencesIslamic Azad UniversityShahrekordIran

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