CXCR1/2 ligands induce p38 MAPK-dependent translocation and release of opioid peptides from primary granules in vitro and in vivo |
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| Authors: | Rittner Heike L Labuz Dominika Richter Jan F Brack Alexander Schäfer Michael Stein Christoph Mousa Shaaban A |
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| Institution: | 1. Institute of Immunology, University of Kiel, Kiel, Germany;2. Dept. of Othorhinotaryngology, Head and Neck Surgery, Christian-Albrechts-University, Kiel, Germany;3. Dept. of Rheumatology, University Hospital Schleswig-Holstein Campus Lübeck, Lübeck, Germany;4. Institute for Experimental Medicine, Group Inflammatory Carcinogenesis, University of Kiel, Kiel, Germany;1. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC;2. Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC;3. Center for General Education, University of Kang Ning, Taipei, Taiwan, ROC;4. Department of Internal Medicine, Division of Nephrology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, ROC;5. Department of Physiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan, ROC |
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| Abstract: | Polymorphonuclear leukocytes (PMN) can release opioid peptides which bind to opioid receptors on sensory neurons and inhibit inflammatory pain. This release can be triggered by chemokine receptor 1/2 (CXCR1/2) ligands. Our aim was to identify the granule subpopulation containing opioid peptides and to assess whether MAPK mediate the CXCR1/2 ligand-induced release of these peptides. Using double immunofluorescence confocal microscopy, we showed that beta-endorphin (END) and Met-enkephalin (ENK) were colocalized with the primary (azurophil) granule markers CD63 and myeloperoxidase (MPO) within PMN. END and ENK release triggered by a CXCR1/2 ligand in vitro was dependent on the presence of cytochalasin B (CyB) and on p38 MAPK, but not on p42/44 MAPK. In addition, translocation of END and ENK containing primary granules to submembranous regions of the cell was abolished by the p38 MAPK inhibitor SB203580. In vivo CXCL2/3 reduced pain in rats with complete Freund's adjuvant (CFA)-induced hindpaw inflammation. This effect was attenuated by intraplantar (i.pl.) antibodies against END and ENK and by i.pl. p38 MAPK inhibitor treatment. Taken together, these findings indicate that END and ENK are contained in primary granules of PMN, and that CXCR1/2 ligands induce p38-dependent translocation and release of these opioid peptides to inhibit inflammatory pain. |
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| Keywords: | Inflammatory pain Antinociception Neutrophil Chemokine β -Endorphin Met-enkephalin Signalling |
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