PMID- 30270727 OWN - NLM STAT- MEDLINE DCOM- 20190114 LR - 20190114 IS - 1744-8069 (Electronic) IS - 1744-8069 (Linking) VI - 14 DP - 2018 Jan-Dec TI - TLR4/NF-kappaB signaling activation in plantar tissue and dorsal root ganglion involves in the development of postoperative pain. PG - 1744806918807050 LID - 10.1177/1744806918807050 [doi] LID - 1744806918807050 AB - Background Severe postoperative pain remains a clinical problem that impacts patient's rehabilitation. The present work aims to investigate the role of Toll-like receptor-4 (TLR4) activation in wounded plantar tissue and dorsal root ganglion (DRG) in the genesis of postoperative pain and its underlying mechanisms. Results Postoperative pain was induced by plantar incision in rat hind paw. Plantar incision led to increased expression of TLR4 in ipsilateral lumbar 4-5 (L4/L5) DRGs, which occurred at 2 h and was persistent to the third day after surgery. Similar to the change in TLR4 expression, there was also significant increase in phosphorylated nuclear factor-kappa B p65 (p-p65) in DRGs after surgery. Immunofluorescence staining revealed that the increased expressions of TLR4 and p-p65 not only in neuronal cells but also in satellite glial cells in DRG. Furthermore, the enhanced expressions of TLR4 and p-p65 were also detected in plantar tissues around the incision, which was observed starting at 2 h and lasting until the third day after surgery. Prior intrathecal (i.t.) injections of TAK-242 (a TLR4-specific antagonist) or 4',6-diamidino-2-phenylindole-dihydrochloride (PDTC, a nuclear factor-kappa B activation inhibitor) dose dependently alleviated plantar incision-induced mechanical allodynia and thermal hyperalgesia and inhibited the increased expressions of p-p65, tumor necrosis factor-alpha, and interleukin-1 beta in DRG. Prior subcutaneous (s.c.) plantar injection of TAK-242 or PDTC also ameliorated pain-related hypersensitivity following plantar incision. Moreover, the plantar s.c. injection of TAK-242 or PDTC inhibited the increased expressions of p-p65, tumor necrosis factor-alpha, and interleukin-1 beta not only in local wounded plantar tissue but also dramatically in ipsilateral lumbar 4-5 DRGs. Conclusion TLR4/ nuclear factor-kappa B signaling activation in local injured tissue and DRG contribute to the development of postoperative pain via regulating pro-inflammatory cytokines release. Targeting TLR4/ nuclear factor-kappa B signaling in local tissue at early stage of surgery may be an effective strategy for the treatment of postoperative pain. FAU - Xing, Fei AU - Xing F AD - 1 Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. AD - 2 Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China. FAU - Zhang, Wei AU - Zhang W AD - 1 Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. AD - 3 Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. FAU - Wen, Jing AU - Wen J AD - 1 Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. FAU - Bai, Liying AU - Bai L AD - 1 Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. FAU - Gu, Hanwen AU - Gu H AD - 1 Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. AD - 2 Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China. FAU - Li, Zhisong AU - Li Z AD - 1 Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. AD - 3 Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. FAU - Zhang, Jian AU - Zhang J AD - 2 Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China. FAU - Tao, Yuan-Xiang AU - Tao YX AD - 3 Neuroscience Research Institute, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China. FAU - Xu, Ji-Tian AU - Xu JT AD - 1 Department of Anesthesiology, The First Affiliated Hospital, Zhengzhou University, Zhengzhou, China. AD - 2 Department of Physiology and Neurobiology, School of Basic Medical Sciences, Zhengzhou University, Zhengzhou, China. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20181001 PL - United States TA - Mol Pain JT - Molecular pain JID - 101242662 RN - 0 (Antioxidants) RN - 0 (Cytokines) RN - 0 (Enzyme Inhibitors) RN - 0 (Glial Fibrillary Acidic Protein) RN - 0 (Lectins) RN - 0 (NF-kappa B) RN - 0 (Sulfonamides) RN - 0 (Thiocarbamates) RN - 0 (Toll-Like Receptor 4) RN - 0 (ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate) RN - 135467-92-4 (prolinedithiocarbamate) RN - 9DLQ4CIU6V (Proline) SB - IM MH - Analysis of Variance MH - Animals MH - Antioxidants/pharmacology MH - Cytokines/metabolism MH - Disease Models, Animal MH - Dose-Response Relationship, Drug MH - Enzyme Activation/drug effects MH - Enzyme Inhibitors/pharmacology MH - Ganglia, Spinal/*metabolism MH - Glial Fibrillary Acidic Protein/metabolism MH - Lectins/metabolism MH - Male MH - NF-kappa B/*metabolism MH - Pain Threshold/drug effects MH - Pain, Postoperative/*pathology MH - Plantar Plate/*metabolism MH - Proline/analogs & derivatives/pharmacology MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction/drug effects/*physiology MH - Sulfonamides/pharmacology MH - Thiocarbamates/pharmacology MH - Toll-Like Receptor 4/antagonists & inhibitors/*metabolism PMC - PMC6196615 OTO - NOTNLM OT - Postoperative pain OT - Toll-like receptor-4/nuclear factor-kappa B signaling OT - dorsal root ganglion OT - plantar incision OT - plantar tissue EDAT- 2018/10/03 06:00 MHDA- 2019/01/15 06:00 PMCR- 2018/10/18 CRDT- 2018/10/02 06:00 PHST- 2018/10/03 06:00 [pubmed] PHST- 2019/01/15 06:00 [medline] PHST- 2018/10/02 06:00 [entrez] PHST- 2018/10/18 00:00 [pmc-release] AID - 10.1177_1744806918807050 [pii] AID - 10.1177/1744806918807050 [doi] PST - ppublish SO - Mol Pain. 2018 Jan-Dec;14:1744806918807050. doi: 10.1177/1744806918807050. Epub 2018 Oct 1.