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Exploring the Function of a Novel Chronic Pain Player

dc.contributor.advisorSchmidt, Manuela Prof. Dr.
dc.contributor.authorHütte, Meike
dc.titleExploring the Function of a Novel Chronic Pain Playerde
dc.contributor.refereeSchmidt, Manuela Prof. Dr.
dc.description.abstractengAs currently available chronic pain medication is associated with undesirable side effects and suboptimal efficacy, the improvement of treatment options is a major task in the pain research community. The basis for the latter is an advanced understanding of the molecular mechanisms underlying chronic pain states. The approach to target molecules that are specifically involved in the pathological form of pain is highly important in order to maintain an individual’s ability to process acute nociceptive pain. Such a strategy ideally allows for novel drug target identification, and thereby decreased side effects and enhanced therapeutic outcomes. Here, an uncharacterized mitochondrial transmembrane protein (TM) was investigated with regard to its role in chronic inflammatory and neuropathic pain. In a previous quantitative proteomics study, TM and other mitochondrial proteins showed differential expression in two mouse models of chronic pain. This finding was in line with the growing evidence for the connection between mitochondrial dysfunction and diverse chronic pain conditions. TM was characterized in vivo by generating knock out (KO) mice with the CRISPR/Cas9 technology. Effective gene ablation was confirmed by, genomic sequencing, quantitative RT-PCR and in situ hybridization. Neuropathic pain was induced by a spared nerve injury (SNI-model) and the intraplantar injection of CFA (Complete Freund’s Adjuvant) that causes inflammatory pain. Sham operated/vehicle injected mice served as controls. Subsequently, a battery of behavioral paradigms including measures of stimulus-evoked and spontaneous pain was performed. Strikingly, a specific attenuation of mechanical hypersensitivity upon induction of inflammatory pain and in the initial stage of neuropathic pain (7 days post surgery, marked by pronounced inflammation) was shown in TM KO mice. However, later neuropathic pain phases were not affected. Moreover, other investigated pain modalities such as heat hypersensitivity, NEP and movement-evoked pain were unaltered in TM-deficient mice. Besides, several in vitro techniques were applied to study the molecular basis for the behavioral phenotype. They revealed altered mRNA levels of several prototypic inflammatory mediators and components implicated in mitochondrial function in dorsal root ganglia (DRG) and sciatic nerves (SN) of TM KO mice. Mitochondrial dysfunction and potential alteration of neuronal excitability could not be approved with the applied methods. However, decreased activation of a specific nociceptor subpopulation was shown in sensory neurons upon TM ablation, which could be rescued by application of the cytokine TNFα (downregulated mRNA level). Further research is needed to understand the molecular mechanism underlying the specific alleviation of mechanical hypersensitivity during the early inflammatory stage of neuropathic pain and CFA-evoked inflammatory pain in TM KO mice. Yet, these results propose a novel and pivotal implication for TM in modality-specific pain
dc.contributor.coRefereeMoser, Tobias Prof. Dr.
dc.subject.engChronic Painde
dc.subject.engInflammatory Painde
dc.subject.engNeuropathic Painde
dc.subject.engSensory Neuronsde
dc.affiliation.instituteBiologische Fakultät für Biologie und Psychologiede
dc.subject.gokfullBiologie (PPN619462639)de

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