International Journal of Medical Sciences

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23 October 2018

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Int J Med Sci 2018; 15(9):875-882. doi:10.7150/ijms.23074

Research Paper

Morphine Induces Fibroblast Activation through Up-regulation of Connexin 43 Expression: Implication of Fibrosis in Wound Healing

Ping-Ching Wu1,2,3*, Wen-Li Hsu4*, Chun-Lin Chen5,6, Chen-Fuh Lam7, Yaw-Bin Huang6,8, Chien-Chi Huang9, Ming-Hong Lin10,11✉, Ming-Wei Lin6,12✉

1. Department of Biomedical Engineering, National Cheng Kung University, Tainan, Taiwan
2. Institute of Oral Medicine and Department of Stomatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University Tainan, Taiwan
3. Medical Device Innovation Center, Taiwan Innovation Center of Medical Devices and Technology, National Cheng Kung University Hospital, National Cheng Kung University, Tainan, Taiwan
4. Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan.
5. Department of Biological Science, National Sun Yat-sen University, Kaohsiung, Taiwan
6. Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, Taiwan
7. Department of Anesthesiology, E-Da Hospital/E-Da Cancer Hospital/I-Shou University, Kaohsiung, Taiwan.
8. School of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
9. Department of Anesthesiology, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan
10. Department of Microbiology and Immunology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
11. Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
12. Department of Medical Research, E-Da Hospital/E-Da Cancer Hospital, Kaohsiung, Taiwan
*Equal contributors

Abstract

Morphine is the most effective drugs for attenuating various types of severe pain, but morphine abuse carries a high risk of systemic fibrosis. Our previous have indicated that systemic administration of morphine hinders angiogenesis and delays wound healing. Here we have explained the pathological mechanism underlying the effect of morphine on wound healing. To determine how morphine affects wound healing, we first created a wound in mice treated them with a combination of a low doses (5 mg/kg/day) and high doses (20 or 30 mg/kg/day) of morphine. An In vivo study revealed that high-dose morphine-induced abnormal myofibroblasts persist after the end of wound healing because of connexin 43 (Cx43) upregulation. High-dose morphine-induced Cx43 increased the expression levels of focal adhesion molecules, namely fibronectin and alpha-smooth muscle actin (α-SMA) through the activation of transforming growth factor (TGF)-β1 signaling. In addition, we found that Cx43 contributed to TGF-βRII/ Smad2/3 signaling for regulating the differentiation of fibroblasts into myofibroblasts during high-dose morphine exposure. In conclusion, the abnormal regulation of Cx43 by morphine may induce systemic fibrosis because of abnormal myofibroblast function.

Keywords: Morphine, Wound Healing, Fibrosis, Cx43

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How to cite this article:
Wu PC, Hsu WL, Chen CL, Lam CF, Huang YB, Huang CC, Lin MH, Lin MW. Morphine Induces Fibroblast Activation through Up-regulation of Connexin 43 Expression: Implication of Fibrosis in Wound Healing. Int J Med Sci 2018; 15(9):875-882. doi:10.7150/ijms.23074. Available from http://www.medsci.org/v15p0875.htm