title: Orthopedic surgery modulates neuropeptides and BDNF expression at the spinal and hippocampal levels.
abstract: Pain is a critical component hindering recovery and regaining of function after surgery, particularly in the elderly. Understanding the role of pain signaling after surgery may lead to novel interventions for common complications such as delirium and postoperative cognitive dysfunction. Using a model of tibial fracture with intramedullary pinning in male mice, associated with cognitive deficits, we characterized the effects on the primary somatosensory system. Here we show that tibial fracture with pinning triggers cold allodynia and up-regulates nerve injury and inflammatory markers in dorsal root ganglia (DRGs) and spinal cord up to 2 wk after intervention. At 72 h after surgery, there is an increase in activating transcription factor 3 (ATF3), the neuropeptides galanin and neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), as well as neuroinflammatory markers including ionized calcium-binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and the fractalkine receptor CX3CR1 in DRGs. Using an established model of complete transection of the sciatic nerve for comparison, we observed similar but more pronounced changes in these markers. However, protein levels of BDNF remained elevated for a longer period after fracture. In the hippocampus, BDNF protein levels were increased, yet there were no changes in Bdnf mRNA in the parent granule cell bodies. Further, c-Fos was down-regulated in the hippocampus, together with a reduction in neurogenesis in the subgranular zone. Taken together, our results suggest that attenuated BDNF release and signaling in the dentate gyrus may account for cognitive and mental deficits sometimes observed after surgery.
authors: Department of Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden; mingdong.zhang@ki.se tomas.hokfelt@ki.se niccolo.terrando@duke.edu.
authors: Ming-Dong
authors: MD
authors: Zhang
authors: Department of Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden.
authors: Swapnali
authors: S
authors: Barde
authors: Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham, NC 27710.
authors: Ting
authors: T
authors: Yang
authors: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710.
authors: Beilei
authors: B
authors: Lei
authors: Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Function Perioperative Medicine and Intensive Care, Karolinska University Hospital, Stockholm 171 76, Sweden.
authors: Lars I
authors: LI
authors: Eriksson
authors: Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710.
authors: Joseph P
authors: JP
authors: Mathew
authors: Institute of Clinical Neurobiology, University of Würzburg, 97078 Wuerzburg, Germany.
authors: Thomas
authors: T
authors: Andreska
authors: Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158; Department of Neurology, University of California, San Francisco, CA 94158.
authors: Katerina
authors: K
authors: Akassoglou
authors: Department of Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Molecular Neurosciences, Center for Brain Research, Medical University of Vienna, A-1090 Vienna, Austria.
authors: Tibor
authors: T
authors: Harkany
authors: Department of Neuroscience, Karolinska Institutet, Stockholm 171 77, Sweden; mingdong.zhang@ki.se tomas.hokfelt@ki.se niccolo.terrando@duke.edu.
authors: Tomas G M
authors: TG
authors: Hökfelt
authors: Department of Physiology and Pharmacology, Section for Anesthesiology and Intensive Care Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Anesthesiology, Duke University Medical Center, Durham, NC 27710; mingdong.zhang@ki.se tomas.hokfelt@ki.se niccolo.terrando@duke.edu.
authors: Niccolò
authors: N
authors: Terrando
mesh_terms: D051700:Activating Transcription Factor 3 / Q000235:genetics / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D000073883:CX3C Chemokine Receptor 1 / Q000235:genetics / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism; D060825:Cognitive Dysfunction / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018891:Dentate Gyrus / Q000378:metabolism* / Q000503:physiopathology; D005594:Fracture Fixation, Intramedullary / Q000009:adverse effects; D019004:Galanin / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism* / Q000503:physiopathology; D005786:Gene Expression Regulation; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics / Q000378:metabolism; D006930:Hyperalgesia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D010146:Pain / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012584:Sciatic Nerve / Q000293:injuries / Q000378:metabolism; D015398:Signal Transduction; D013116:Spinal Cord / Q000378:metabolism / Q000503:physiopathology; D013978:Tibial Fractures / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000601:surgery*
chemical_list: D051700:Activating Transcription Factor 3; C491049:Aif1 protein, mouse; C103002:Atf3 protein, mouse; D019208:Brain-Derived Neurotrophic Factor; D000073883:CX3C Chemokine Receptor 1; D002135:Calcium-Binding Proteins; C471885:Cx3cr1 protein, mouse; D005904:Glial Fibrillary Acidic Protein; D008840:Microfilament Proteins; D009478:Neuropeptide Y; D016760:Proto-Oncogene Proteins c-fos; D019004:Galanin
keywords: delirium; memory; nerve injury; neurogenesis; postoperative pain