Contributions of p38 and ERK to the antinociceptive effects of TGF-β1 in chronic constriction injury-induced neuropathic rats

The Journal of Headache and Pain

Research Article

Hsiao-Mei Kuo¹  Shi-Ying Huang²  Chun-Sung Sung³  Wu-Fu Chen⁴  Nan-Fu Chen⁵  Chun-Hong Chen⁶  Chien-Wei Feng⁶  Han-Chun Hung⁶  Zhi-Hong Wen⁷  Kuan-Hao Tsui⁸  Ching-Hsiang Lu⁹  Chun-Lin Chen⁹  Hui-Min David Wang^1,10 

[1] Center for Neuroscience, National Sun Yat-sen University, #70 Lien-Hai Rd, 80424, Kaohsiung, Taiwan;Center for Neuroscience, National Sun Yat-sen University, #70 Lien-Hai Rd, 80424, Kaohsiung, Taiwan;College of Oceanology and Food Scienece, Quanzhou Normal University, 362000, Quanzhou, China;Department of Anesthesiology, Taipei Veterans General Hospital, 11217, Taipei, Taiwan;School of Medicine, National Yang-Ming University, 11221, Taipei, Taiwan;Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, 80424, Kaohsiung, Taiwan;Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 83301, Kaohsiung, Taiwan;Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, 80424, Kaohsiung, Taiwan;Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, 80284, Kaohsiung, Taiwan;Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, 11490, Taipei, Taiwan;Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, 80424, Kaohsiung, Taiwan;Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, 80424, Kaohsiung, Taiwan;Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, 80424, Kaohsiung, Taiwan;Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, 80424, Kaohsiung, Taiwan;Marine Biomedical Laboratory and Center for Translational Biopharmaceuticals, Department of Marine Biotechnology and Resources, National Sun Yat-sen University, 80424, Kaohsiung, Taiwan;Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, 81362, Kaohsiung, Taiwan;Department of Obstetrics and Gynecology and Institute of Clinical Medicine, National Yang-Ming University, 11221, Taipei, Taiwan;Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, 90741, Pingtung, Taiwan;Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, 80284, Kaohsiung, Taiwan;Graduate Institute of Biomedical Engineering, National Chung Hsing University, 40227, Taichung, Taiwan;Center for Stem Cell Research, Kaohsiung Medical University, 80708, Kaohsiung, Taiwan;College of Oceanology and Food Scienece, Quanzhou Normal University, 362000, Quanzhou, China;

关键词: Transforming growth factor-β;    p38;    Extracellular signal-regulated kinase;    Chronic constriction injury;    Neuropathic pain;   

DOI  :  10.1186/s10194-016-0665-2

 received in 2016-04-18, accepted in 2016-08-09,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundTransforming growth factor-βs (TGF-βs) are a group of multifunctional proteins that have neuroprotective roles in various experimental models. We previously reported that intrathecal (i.t.) injections of TGF-β1 significantly inhibit neuropathy-induced thermal hyperalgesia, spinal microglia and astrocyte activation, as well as upregulation of tumor necrosis factor-α. However, additional cellular mechanisms for the antinociceptive effects of TGF-β1, such as the mitogen-activated protein kinase (MAPK) pathway, have not been elucidated. During persistent pain, activation of MAPKs, especially p38 and extracellular signal-regulated kinase (ERK), have crucial roles in the induction and maintenance of pain hypersensitivity, via both nontranscriptional and transcriptional regulation. In the present study, we used a chronic constriction injury (CCI) rat model to explore the role of spinal p38 and ERK in the analgesic effects of TGF-β1.MethodsWe investigated the cellular mechanisms of the antinociceptive effects of i.t. injections of TGF-β1 in CCI induced neuropathic rats by spinal immunohistofluorescence analyses.ResultsThe results demonstrated that the antinociceptive effects of TGF-β1 (5 ng) were maintained at greater than 50 % of the maximum possible effect in rats with CCI for at least 6 h after a single i.t. administration. Thus, we further examined these alterations in spinal p38 and ERK from 0.5 to 6 h after i.t. administration of TGF-β1. TGF-β1 significantly attenuated CCI-induced upregulation of phosphorylated p38 (phospho-p38) and phosphorylated ERK (phospho-ERK) expression in the dorsal horn of the lumbar spinal cord. Double immunofluorescence staining illustrated that upregulation of spinal phospho-p38 was localized to neurons, activated microglial cells, and activated astrocytes in rats with CCI. Additionally, increased phospho-ERK occurred in activated microglial cells and activated astrocytes. Furthermore, i.t. administration of TGF-β1 markedly inhibited phospho-p38 upregulation in neurons, microglial cells, and astrocytes. However, i.t. injection of TGF-β1 also reduced phospho-ERK upregulation in microglial cells and astrocytes.ConclusionsThe present results demonstrate that suppressing p38 and ERK activity affects TGF-β1-induced analgesia during neuropathy.

【 授权许可】

CC BY   
© The Author(s). 2016