title: Activation of glial glutamate transporter via MAPK p38 prevents enhanced and long-lasting non-evoked resting pain after surgical incision in rats.
abstract: Pain after surgery has recently become a major issue not only due to lack of treatment success in the acute phase; even more alarming is the large number of patients developing prolonged pain after surgery. Because spinal glutamate as well as spinal glia plays a major role in acute incisional pain, we investigated the role of the spinal glial glutamate transporters (GT), GLAST, GLT-1, for acute and prolonged pain and hyperalgesia caused by an incision. Spinal administration of the GT-inhibitor DL-TBOA increased non-evoked pain but not evoked pain behavior (hyperalgesia) up to 2 weeks after incision. In accordance, spinal GLAST (and to a lesser degree GLT-1) were upregulated after incision for several days. Long-term incision induced GT upregulation was prevented by long-lasting p38-inhibitor administration but not by long-lasting ERK1/2-inhibition after incision. In accordance, daily treatment with the p38-inhibitor (but not the ERK1/2 inhibitor) prolonged non-evoked but not evoked pain behavior after incision. In electrophysiological experiments, spontaneous activity of high threshold (HT) (but not wide dynamic range (WDR)) neurons known to transmit incision induced non-evoked pain was increased after prolonged treatment with the p38-inhibitor. In conclusion, our findings indicate a new spinal pathway by which non-evoked pain behavior after incision is modulated. The pathway is modality (non-evoked pain) and neuron (HT) specific and disturbance contributes to prolonged long-term pain after surgical incision. This may have therapeutic implications for the treatment of acute and - even more relevant - for prevention of chronic pain after surgery in patients.
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Muenster, Germany; Department of Anesthesiology, Perioperative and General Intensive Care Medicine, University Hospital Salzburg and Paracelsus Private Medical University, Muellner Hauptstr. 48, 5020 Salzburg, Austria.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Reichl
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Muenster, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Segelcke
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Muenster, Germany.
authors.forename: Viktor
authors.initials: V
authors.lastname: Keller
authors.affiliation: Department of Anesthesiology and Intensive Care, Faculty of Medicine at Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer, 68167 Mannheim, Germany.
authors.forename: Robin
authors.initials: R
authors.lastname: Jonas
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Muenster, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Boecker
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Muenster, Germany.
authors.forename: Manuel
authors.initials: M
authors.lastname: Wenk
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Muenster, Germany.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Evers
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Treatment, Ruhr-University Bochum, BG-Kliniken Bergmannsheil, Buerkle-de-la-Camp-Platz 1, Bochum, Germany.
authors.forename: Peter K
authors.initials: PK
authors.lastname: Zahn
authors.affiliation: Department of Anesthesiology, Intensive Care and Pain Medicine, University Hospital Muenster, Albert-Schweitzer-Campus 1, Gebäude A1, 48149 Muenster, Germany. Electronic address: pogatzki@anit.uni-muenster.de.
authors.forename: Esther M
authors.initials: EM
authors.lastname: Pogatzki-Zahn
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001224:Aspartic Acid / Q000494:pharmacology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D027341:Excitatory Amino Acid Transporter 1 / Q000378:metabolism*; D027342:Excitatory Amino Acid Transporter 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology; D005528:Foot; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010149:Postoperative Pain / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D020671:Posterior Horn Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D015854:Up-Regulation / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D027341:Excitatory Amino Acid Transporter 1; D027342:Excitatory Amino Acid Transporter 2; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; C493395:Slc1a2 protein, rat; C493392:Slc1a3 protein, rat; C120673:benzyloxyaspartate; D001224:Aspartic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: DL-TBOA (PubChem CID 5311218); Glia interaction; Glutamate transporter; Incision model; Neurotransmitter; PD98059 (PubChem CID 4713); Postoperative pain; SB203580 (PubChem CID 176155)