TY - THES A1 - Mohammadi, Milad T1 - Role of oxidized phospholipids in inflammatory pain T1 - Rolle von oxidierten Phospholipiden bei entzündlichen Schmerzen N2 - Introduction: During inflammation, reactive oxygen species (ROS) such as Hydrogen peroxide accumulate at the inflammation site and by oxidizing lipids, they produce metabolites such as 4-hydroxynonenal (4-HNE) and oxidized phospholipids (OxPLs). Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ligand gated ion channels that are expressed on nociceptors and their activation elicits pain. Hydrogen peroxide and 4-HNE are endogenous ligands for TRPA1 and their role in inflammatory pain conditions has been shown. OxPLs play a major pro-inflammatory role in many pathologies including atherosclerosis and multiple sclerosis. E06/T15 is a mouse IgM mAb that specifically binds oxidized phosphatidylcholine. D-4F is an apolipoprotein A-I mimetic peptide with a very high affinity for OxPLs and possess anti-inflammatory properties. E06 mAb and D-4F peptide protect against OxPLs-induced damage in atherosclerosis in vivo. Methods: To investigate the role of ROS and their metabolites in inflammatory pain, I utilized a combination of diverse and complex behavioral pain measurements and binding assays. I examined E06 mAb and D-4F as local treatment options for hypersensitivity evoked by endogenous and exogenous activators of TRPA1 and TRPV1 as well as in inflammatory and OxPL-induced pain models in vivo. 4-HNE, hydrogen peroxide as ROS source and mustard oil (AITC) were used to activate TRPA1, while capsaicin was used to activate TRPV1. Results: Intraplantar injection of oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (OxPAPC) into rats’ hind paw elicited thermal and mechanical hypersensitivity. Genetic and pharmacological evidence in vivo confirmed the role of TRPA1 in OxPLs-induced hypersensitivity. OxPLs formation increased in complete Freund’s adjuvant (CFA)-induced inflamed rats’ paw. E06 mAb and D-4F prevented OxPAPC–induced mechanical and thermal hypersensitivity (hyperalgesia) as well as CFA-induced mechanical hypersensitivity. Also, all irritants induced thermal and mechanical hypersensitivity as well as affective-emotional responses and spontaneous nocifensive behaviors. E06 mAb blocked prolonged mechanical hypersensitivity by all but hydrogen peroxide. In parallel, D-4F prevented mechanical hypersensitivity induced by all irritants as well as thermal hypersensitivity induced by capsaicin and 4-HNE. In addition, competitive binding assays showed that all TRPA1/V1 agonists induced prolonged formation of OxPLs in the paw tissue explaining the anti-nociceptive properties of E06 mAb and D-4F. Finally, the potential of gait analysis as a readout for non-provoked pain behavioral measurements were examined. Conclusion and implications: OxPLs were characterized as novel targets in inflammatory pain. Treatment with the monoclonal antibody E06 or apolipoprotein A-I mimetic peptide D-4F are suggested as potential inflammatory pain medications. OxPLs’ role in neuropathic pain is yet to be investigated. N2 - Im entzündeten Gewebe akkumulieren reaktive Sauerstoffspezies (ROS) sowie oxidierte Phospholipide (OxPLs). ROS und in der Reaktionskette nachgeschaltete Verbindungen, wie 4- Hydroxynonenal (4-HNE) aktivieren Transiente Rezeptor Potential (TRP) Ionenkanäle: Ankyrin 1 (TRPA1) und Vanilloid 1 (TRPV1). Diese TRP-Kanäle werden auf Nozizeptoren exprimiert und rufen Schmerz z.B. bei Entzündung hervor. OxPLs sind an vielen entzündungsfördernden Prozessen maßgebend beteiligt und spielen eine Schlüsselrolle bei Pathologie von Atherosklerose und Multipler Sklerose. E06/T15 ist ein Maus IgM-mAb, welcher spezifisch an oxidierte Phosphatidylcholine bindet. D-4F ist ein Apolipoprotein A-I (ApoA-I) mimetisches Peptid, das eine sehr hohe Affinität für OxPLs aufweist und auch entzündungshemmende Eigenschaften besitzt. E06 mAb und D-4F schützen vor Atherosklerose in vivo. Um die mögliche Rolle von OxPLs beim Entzündungsschmerz zu untersuchen, verwendete ich eine Kombination von verschiedenen und komplexen Schmerzverhaltensmessungen, Bindungsassays und immunhistologische Färbungen. ... KW - Inflammatory pain KW - Oxidized phospholipids KW - reactive oxygen species KW - ROS KW - 4-HNE KW - HNE KW - OxPL Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-192402 ER - TY - THES A1 - Frank, Johanna T1 - Untersuchung der Kleinfaserpathologie beim Fibromyalgie-Syndrom T1 - Examination of small fiber pathology in fibromyalgia syndrome N2 - Die Studienergebnisse stützen das Konzept, dass das periphere Nervensystem zu Schmerzen beim Fibromyalgie-Syndrom (FMS) beiträgt. An der Neurologischen Universitätsklinik Würzburg wurden 53 FMS Patientinnen und 35 gesunde Kontrollen rekrutiert, ausführlich anamnestiziert inklusive spezieller Schmerzfragebögen, neurologisch und mittels spezieller Tests auf eine Störung der kleinkalibrigen A-delta- und C-Nervenfasern untersucht. Hierzu gehörte eine quantitative sensorische Testung mit Pleasant touch Untersuchung und die schmerz-assoziierten elektrisch-evoziierten Potentiale für die Kleinfaserfunktion und die corneale confocale Mikroskopie, sowie die Analyse von Hautstanbiopsien für die Kleinfasermorphologie. Im Unterschied zu gesunden Kontrollen wiesen die FMS Patientinnen eine Reduktion, als auch eine Funktionsänderung der kleinkalibrigen Nervenfasern auf. Des Weiteren konnten wir aus der heterogenen Patientenpopulation anhand von unterschiedlichen Nervenfaserdichten der Haut eine Subgruppe mit generalisierter Reduktion der Hautinnervation identifizieren, die besonders schwer betroffen ist. Diese Subgruppenanalysen können künftig von großer Bedeutung für die Therapiewahl sein. N2 - The results of this study support the concept of an involvement of the peripheral nervous system in the development of pain in fibromyalgia sydrome (FMS). At the Department of Neurology, University of Würzburg, Germany, we recruted 53 FMS patients and 35 healty controls, who filled in pain questionnaires and underwent thorough history taking, neurologic examination and special small fiber tests, which tested the function and morphology of the A-delta and C-fibers. In detail, tests consisted of quantitative sensory testing with pleasant touch examination and pain-related evoked potentials for small fiber function, and corneal confocal microscopy and skin punch biopsy for fiber morphology. In contrast to healthy controls, FMS patients showed a reduction and change in morphology of the small fibers. Further, we identified a subgroup of patients with generalized reduction of skin innervation, who showed higher disease burden than FMS patients with normal skin innervation. The identification of FMS subgroups may be of great relevance for future treatment stratification. KW - Fibromyalgie KW - Kleinfaseruntersuchungen KW - small fiber pathology KW - kleinkalibrige Nervenfasern KW - corneale confocale Mikroskopie KW - Hautstanzbiopsie KW - schmerz-assoziierte elektrisch-evozierte Potenziale KW - Quantitative sensorische Testung KW - pleasant touch KW - small fiber tests KW - skin punch biopsy KW - corneal confocal microscopy KW - quantitative sensory testing KW - pain-related evoked potentials Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-192653 PB - Annals of Neurology, The Journal of Rheumatology ER -