title: The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons.
abstract: Sensitization of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid mediator whose role in peripheral nociceptive sensitization is not well understood to date. Two major G-protein-coupled receptors for leukotriene B4 have been identified: the high-affinity receptor BLT1 and the low-affinity receptor BLT2. Transcriptional screening for the expression G-protein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for leukotriene B4 (100-200 nm). Selective antagonists and neurons from knock-out mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, leukotriene B4-induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knock-out mice. Importantly, higher leukotriene B4 concentrations (>0.5 μm) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2 activation inhibited protein kinase C- and protein kinase A-mediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data, immunohistochemical analysis showed that both leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system.
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Zinn
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Sisignano
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Kern
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Pierre
authors.affiliation: the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Sorin
authors.initials: S
authors.lastname: Tunaru
authors.affiliation: the Fraunhofer Institute of Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology, 60590 Frankfurt, Germany, and.
authors.forename: Holger
authors.initials: H
authors.lastname: Jordan
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Jing
authors.initials: J
authors.lastname: Suo
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Elsa-Marie
authors.initials: EM
authors.lastname: Treutlein
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.
authors.forename: Nerea
authors.initials: N
authors.lastname: Ferreiros
authors.affiliation: the Department for Anaesthesiology and Critical Care Medicine, Hannover Medical School, 30625 Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Leffler
authors.affiliation: the Fraunhofer Institute of Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology, 60590 Frankfurt, Germany, and.
authors.forename: Natasja
authors.initials: N
authors.lastname: DeBruin
authors.affiliation: the Department of Pharmacology, Max Planck Institute for Heart and Lung Research, 61231 Bad Nauheim, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany.|the Fraunhofer Institute of Molecular Biology and Applied Ecology, Project Group Translational Medicine and Pharmacology, 60590 Frankfurt, Germany, and.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: From the Institut für Klinische Pharmakologie, Pharmazentrum Frankfurt, Klinikum der Goethe-Universität Frankfurt, 60590 Frankfurt, Germany, scholich@em.uni-frankfurt.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D005727:Ganglia, Spinal / Q000378:metabolism*; D006930:Hyperalgesia / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D007975:Leukotriene B4 / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism; D018102:Receptors, Leukotriene B4 / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism
chemical_list: C503704:Ltb4r1 protein, mouse; C412867:Ltb4r2 protein, mouse; D018102:Receptors, Leukotriene B4; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D007975:Leukotriene B4; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C; D019703:Calcineurin
keywords: G protein-coupled receptor (GPCR); calcineurin; inflammation; leukotriene; pain