title: The G2A receptor (GPR132) contributes to oxaliplatin-induced mechanical pain hypersensitivity.
abstract: Chemotherapy-induced peripheral neuropathic pain (CIPN) is a common and severe debilitating side effect of many widely used cytostatics. However, there is no approved pharmacological treatment for CIPN available. Among other substances, oxaliplatin causes CIPN in up to 80% of treated patients. Here, we report the involvement of the G-protein coupled receptor G2A (GPR132) in oxaliplatin-induced neuropathic pain in mice. We found that mice deficient in the G2A-receptor show decreased mechanical hypersensitivity after oxaliplatin treatment. Lipid ligands of G2A were found in increased concentrations in the sciatic nerve and dorsal root ganglia of oxaliplatin treated mice. Calcium imaging and patch-clamp experiments show that G2A activation sensitizes the ligand-gated ion channel TRPV1 in sensory neurons via activation of PKC. Based on these findings, we conclude that targeting G2A may be a promising approach to reduce oxaliplatin-induced TRPV1-sensitization and the hyperexcitability of sensory neurons and thereby to reduce pain in patients treated with this chemotherapeutic agent.
authors.affiliation: Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital, Goethe-University, D-60590, Frankfurt am Main, Germany.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Hohmann
authors.affiliation: Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital, Goethe-University, D-60590, Frankfurt am Main, Germany.
authors.forename: Carlo
authors.initials: C
authors.lastname: Angioni
authors.affiliation: 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: F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Seungkyu
authors.identifier: 0000-0002-1929-3320
authors.initials: S
authors.lastname: Lee
authors.affiliation: F. M. Kirby Neurobiology Center, Children's Hospital Boston, and Department of Neurobiology, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Woolf
authors.affiliation: 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: Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital, Goethe-University, D-60590, Frankfurt am Main, Germany.|Fraunhofer Institute for Molecular Biology and Applied Ecology - Project Group Translational Medicine and Pharmacology (IME-TMP), Frankfurt am Main, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Geisslinger
authors.affiliation: Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital, Goethe-University, D-60590, Frankfurt am Main, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Scholich
authors.affiliation: Institute of Clinical Pharmacology, pharmazentrum frankfurt/ZAFES, University Hospital, Goethe-University, D-60590, Frankfurt am Main, Germany. marco.sisignano@med.uni-frankfurt.de.
authors.forename: Marco
authors.identifier: 0000-0002-7581-0951
authors.initials: M
authors.lastname: Sisignano
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000172:deficiency / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D005727:Ganglia, Spinal / Q000187:drug effects / Q000473:pathology; D006930:Hyperalgesia / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D044243:Linoleic Acids, Conjugated; D008810:Mice, Inbred C57BL; D009437:Neuralgia / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000009:adverse effects*; D000077150:Oxaliplatin; D011493:Protein Kinase C / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency / Q000378:metabolism*; D012584:Sciatic Nerve / Q000187:drug effects / Q000473:pathology; D011984:Sensory Receptor Cells / Q000378:metabolism; D050916:TRPV Cation Channels / Q000172:deficiency / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C115270:G2A receptor; D044243:Linoleic Acids, Conjugated; D009944:Organoplatinum Compounds; D043562:Receptors, G-Protein-Coupled; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D000077150:Oxaliplatin; C024347:9-hydroxy-10,12-octadecadienoic acid; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C