@article{OehlerKlokaMohammadietal.2020, author = {Oehler, Beatrice and Kloka, Jan and Mohammadi, Milad and Ben-Kraiem, Adel and Rittner, Heike L.}, title = {D-4F, an ApoA-I mimetic peptide ameliorating TRPA1-mediated nocifensive behaviour in a model of neurogenic inflammation}, series = {Molecular Pain}, volume = {16}, journal = {Molecular Pain}, doi = {10.1177/1744806920903848}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-236061}, pages = {1-11}, year = {2020}, abstract = {Background High doses of capsaicin are recommended for the treatment of neuropathic pain. However, low doses evoke mechanical hypersensitivity. Activation of the capsaicin chemosensor transient receptor potential vanilloid 1 (TRPV1) induces neurogenic inflammation. In addition to the release of pro-inflammatory mediators, reactive oxygen species are produced. These highly reactive molecules generate oxidised phospholipids and 4-hydroxynonenal (4-HNE) which then directly activate TRP ankyrin 1 (TRPA1). The apolipoprotein A-I mimetic peptide D-4F neutralises oxidised phospholipids. Here, we asked whether D-4F ameliorates neurogenic hypersensitivity in rodents by targeting reactive oxygen species and 4-HNE in the capsaicin-evoked pain model. Results Co-application of D-4F ameliorated capsaicin-induced mechanical hypersensitivity and allodynia as well as persistent heat hypersensitivity measured by Randell-Selitto, von Frey and Hargreaves test, respectively. In addition, mechanical hypersensitivity was blocked after co-injection of D-4F with the reactive oxygen species analogue H2O2 or 4-HNE. In vitro studies on dorsal root ganglion neurons and stably transfected cell lines revealed a TRPA1-dependent inhibition of the calcium influx when agonists were pre-incubated with D-4F. The capsaicin-induced calcium influx in TRPV1-expressing cell lines and dorsal root ganglion neurons sustained in the presence of D-4F. Conclusions D-4F is a promising compound to ameliorate TRPA1-dependent hypersensitivity during neurogenic inflammation.}, language = {en} } @article{OehlerBrackBlumetal.2021, author = {Oehler, Beatrice and Brack, Alexander and Blum, Robert and Rittner, Heike L.}, title = {Pain Control by Targeting Oxidized Phospholipids: Functions, Mechanisms, Perspectives}, series = {Frontiers in Endocrinology}, volume = {11}, journal = {Frontiers in Endocrinology}, issn = {1664-2392}, doi = {10.3389/fendo.2020.613868}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-223432}, year = {2021}, abstract = {Within the lipidome oxidized phospholipids (OxPL) form a class of chemically highly reactive metabolites. OxPL are acutely produced in inflamed tissue and act as endogenous, proalgesic (pain-inducing) metabolites. They excite sensory, nociceptive neurons by activating transient receptor potential ion channels, specifically TRPA1 and TRPV1. Under inflammatory conditions, OxPL-mediated receptor potentials even potentiate the action potential firing rate of nociceptors. Targeting OxPL with D-4F, an apolipoprotein A-I mimetic peptide or antibodies like E06, specifically binding oxidized headgroups of phospholipids, can be used to control acute, inflammatory pain syndromes, at least in rodents. With a focus on proalgesic specificities of OxPL, this article discusses, how targeting defined substances of the epilipidome can contribute to mechanism-based therapies against primary and secondary chronic inflammatory or possibly also neuropathic pain.}, language = {en} } @article{OehlerKistnerMartinetal.2017, author = {Oehler, Beatrice and Kistner, Katrin and Martin, Corinna and Schiller, J{\"u}rgen and Mayer, Rafaela and Mohammadi, Milad and Sauer, Reine-Solange and Filipovic, Milos R. and Nieto, Francisco R. and Kloka, Jan and Pfl{\"u}cke, Diana and Hill, Kerstin and Schaefer, Michael and Malcangio, Marzia and Reeh, Peter W. and Brack, Alexander and Blum, Robert and Rittner, Heike L.}, title = {Inflammatory pain control by blocking oxidized phospholipid-mediated TRP channel activation}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, number = {5447}, doi = {10.1038/s41598-017-05348-3}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158536}, year = {2017}, abstract = {Phospholipids occurring in cell membranes and lipoproteins are converted into oxidized phospholipids (OxPL) by oxidative stress promoting atherosclerotic plaque formation. Here, OxPL were characterized as novel targets in acute and chronic inflammatory pain. Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) and its derivatives were identified in inflamed tissue by mass spectrometry and binding assays. They elicited calcium influx, hyperalgesia and induced pro-nociceptive peptide release. Genetic, pharmacological and mass spectrometric evidence in vivo as well as in vitro confirmed the role of transient receptor potential channels (TRPA1 and TRPV1) as OxPAPC targets. Treatment with the monoclonal antibody E06 or with apolipoprotein A-I mimetic peptide D-4F, capturing OxPAPC in atherosclerosis, prevented inflammatory hyperalgesia, and in vitro TRPA1 activation. Administration of D-4F or E06 to rats profoundly ameliorated mechanical hyperalgesia and inflammation in collagen-induced arthritis. These data reveal a clinically relevant role for OxPAPC in inflammation offering therapy for acute and chronic inflammatory pain treatment by scavenging OxPAPC.}, language = {en} } @article{OehlerMohammadiPerpinaVicianoetal.2017, author = {Oehler, Beatrice and Mohammadi, Milad and Perpina Viciano, Cristina and Hackel, Dagmar and Hoffmann, Carsten and Brack, Alexander and Rittner, Heike L.}, title = {Peripheral interaction of Resolvin D1 and E1 with opioid receptor antagonists for antinociception in inflammatory pain in rats}, series = {Frontiers in Molecular Neuroscience}, volume = {10}, journal = {Frontiers in Molecular Neuroscience}, number = {242}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-158642}, year = {2017}, abstract = {Antinociceptive pathways are activated in the periphery in inflammatory pain, for instance resolvins and opioid peptides. Resolvins are biosynthesized from omega-3 polyunsaturated fatty acids such as eicosapentaenoic acid and docosahexaenoic acid. Resolvin D1 (RvD1) and resolvin E1 (RvE1) initiate the resolution of inflammation and control of hypersensitivity via induction of anti-inflammatory signaling cascades. RvD1 binds to lipoxin A4/annexin-A1 receptor/formyl-peptide receptor 2 (ALX/FPR2), RvE1 to chemerin receptor 23 (ChemR23). Antinociception of RvD1 is mediated by interaction with transient receptor potential channels ankyrin 1 (TRPA1). Endogenous opioid peptides are synthesized and released from leukocytes in the tissue and bind to opioid receptors on nociceptor terminals. Here, we further explored peripheral mechanisms of RvD1 and chemerin (Chem), the ligand of ChemR23, in complete Freund's adjuvant (CFA)-induced hindpaw inflammation in male Wistar rats. RvD1 and Chem ameliorated CFA-induced hypersensitivity in early and late inflammatory phases. This was prevented by peripheral blockade of the μ-opioid peptide receptor (MOR) using low dose local naloxone or by local injection of anti-β-endorphin and anti-met-enkephalin (anti-ENK) antibodies. Naloxone also hindered antinociception by the TRPA1 inhibitor HC-030031. RvD1 did not stimulate the release of β-endorphin from macrophages and neutrophils, nor did RvD1 itself activate G-proteins coupled MOR or initiate β-arrestin recruitment to the membrane. TRPA1 blockade by HC-030031 in inflammation in vivo as well as inhibition of the TRPA1-mediated calcium influx in dorsal root ganglia neurons in vitro was hampered by naloxone. Peripheral application of naloxone alone in vivo already lowered mechanical nociceptive thresholds. Therefore, either a perturbation of the balance of endogenous pro- and antinociceptive mechanisms in early and late inflammation, or an interaction of TRPA1 and opioid receptors weaken the antinociceptive potency of RvD1 and TRPA1 blockers.}, language = {en} } @article{LehmannOehlerZuberetal.2020, author = {Lehmann, Martin and Oehler, Beatrice and Zuber, Jonas and Malzahn, Uwe and Walles, Thorsten and Muellenbach, Ralf M. and Roewer, Norbert and Kredel, Markus}, title = {Redistribution of pulmonary ventilation after lung surgery detected with electrical impedance tomography}, series = {Acta Anaesthesiologica Scandinavica}, volume = {64}, journal = {Acta Anaesthesiologica Scandinavica}, number = {4}, doi = {10.1111/aas.13525}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-213575}, pages = {517-525}, year = {2020}, abstract = {Background: Regional ventilation of the lung can be visualized by pulmonary electrical impedance tomography (EIT). The aim of this study was to examine the post-operative redistribution of regional ventilation after lung surgery dependent on the side of surgery and its association with forced vital capacity. Methods: In this prospective, observational cohort study 13 patients undergoing right and 13 patients undergoing left-sided open or video-thoracoscopic procedures have been investigated. Pre-operative measurements with EIT and spirometry were compared with data obtained 3 days post-operation. The center of ventilation (COV) within a 32 × 32 pixel matrix was calculated from EIT data. The transverse axis coordinate of COV, COVx (left/right), was modified to COVx′ (ipsilateral/contralateral). Thus, COVx′ shows a negative change if ventilation shifts contralateral independent of the side of surgery. This enabled testing with two-way ANOVA for repeated measurements (side, time). Results: The perioperative shift of COVx′ was dependent on the side of surgery (P = .007). Ventilation shifted away from the side of surgery after the right-sided surgery (COVx′-1.97 pixel matrix points, P < .001), but not after the left-sided surgery (COVx′-0.61, P = .425). The forced vital capacity (\%predicted) decreased from 94 (83-109)\% (median [quartiles]; [left-sided]) and 89 (80-97)\% (right-sided surgery) to 61 (59-66)\% and 62 (40-72)\% (P < .05), respectively. The perioperative changes in forced vital capacity (\%predicted) were weakly associated with the shift of COVx′. Conclusion: Only after right-sided lung surgery, EIT showed reduced ventilation on the side of surgery while vital capacity was markedly reduced in both groups.}, language = {en} }