title: Contributions of p38 and ERK to the antinociceptive effects of TGF-β1 in chronic constriction injury-induced neuropathic rats.
abstract: BACKGROUND
  Transforming 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.
  
  
  METHODS
  We investigated the cellular mechanisms of the antinociceptive effects of i.t. injections of TGF-β1 in CCI induced neuropathic rats by spinal immunohistofluorescence analyses.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  The present results demonstrate that suppressing p38 and ERK activity affects TGF-β1-induced analgesia during neuropathy.
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan.|Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan.|Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490, Taiwan.
authors.forename: Nan-Fu
authors.initials: NF
authors.lastname: Chen
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan.|Department of Neurosurgery, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, 83301, Taiwan.
authors.forename: Wu-Fu
authors.initials: WF
authors.lastname: Chen
authors.affiliation: Department of Anesthesiology, Taipei Veterans General Hospital, Taipei, 11217, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.
authors.forename: Chun-Sung
authors.initials: CS
authors.lastname: Sung
authors.affiliation: Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan.
authors.forename: Ching-Hsiang
authors.initials: CH
authors.lastname: Lu
authors.affiliation: Division of Neurosurgery, Department of Surgery, Kaohsiung Armed Forces General Hospital, Kaohsiung, 80284, Taiwan.
authors.forename: Chun-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan.|Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, 80424, Taiwan.
authors.forename: Han-Chun
authors.initials: HC
authors.lastname: Hung
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan.|Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, 80424, Taiwan.
authors.forename: Chien-Wei
authors.initials: CW
authors.lastname: Feng
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan.|Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, 80424, Taiwan.
authors.forename: Chun-Hong
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Veterans General Hospital, Kaohsiung, 81362, Taiwan.|Department of Obstetrics and Gynecology and Institute of Clinical Medicine, National Yang-Ming University, Taipei, 11221, Taiwan.|Department of Pharmacy and Graduate Institute of Pharmaceutical Technology, Tajen University, Pingtung, 90741, Taiwan.
authors.forename: Kuan-Hao
authors.initials: KH
authors.lastname: Tsui
authors.affiliation: Center for Neuroscience, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan.
authors.forename: Hsiao-Mei
authors.initials: HM
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Biomedical Engineering, National Chung Hsing University, Taichung, 40227, Taiwan.|Center for Stem Cell Research, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan.|College of Oceanology and Food Scienece, Quanzhou Normal University, Quanzhou, 362000, China.
authors.forename: Hui-Min David
authors.initials: HM
authors.lastname: Wang
authors.affiliation: Department of Marine Biotechnology and Resources, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan. wzh@mail.nsysu.edu.tw.|Doctoral Degree Program in Marine Biotechnology, National Sun Yat-sen University and Academia Sinica, Kaohsiung, 80424, Taiwan. wzh@mail.nsysu.edu.tw.|Marine Biomedical Laboratory and Center for Translational Biopharmaceuticals, Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, 80424, Taiwan. wzh@mail.nsysu.edu.tw.
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Wen
authors.affiliation: Center for Neuroscience, National Sun Yat-sen University, #70 Lien-Hai Rd, Kaohsiung, 80424, Taiwan. johnjohnkings@gmail.com.|College of Oceanology and Food Scienece, Quanzhou Normal University, Quanzhou, 362000, China. johnjohnkings@gmail.com.
authors.forename: Shi-Ying
authors.initials: SY
authors.lastname: Huang
mesh_terms: D000818:Animals; D003251:Constriction, Pathologic / Q000473:pathology*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D007249:Inflammation / Q000473:pathology*; D008297:Male; D059348:Peripheral Nerve Injuries / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625843:Tgfbr1 protein, rat
keywords: Chronic constriction injury; Extracellular signal-regulated kinase; Neuropathic pain; Transforming growth factor-β; p38