Co-culturing sensory neurons and glial cells on microelectrode arrays platforms for functional studies on pain

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Dokumentart: PhDThesis
Date: 2023-09-20
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Cesare, Paolo (Dr.)
Day of Oral Examination: 2021-09-20
DDC Classifikation: 610 - Medicine and health
Keywords: Schmerz , Nervenzelle , Gliazelle
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One in five adults suffers from chronic pain, which frequently aggravates into neuropathic pain. This constitutes a significant cause of long-term sick leave and forced early retirement, placing a financial burden on both individuals and healthcare systems. Many analgesic compounds are already available, which, although they do have therapeutic utility in some acute pain states, are ineffective in between one and two-thirds of patients suffering from chronic pain conditions. These drugs also suffer from drawbacks in clinical use, with common side-effects, especially in long-term applications. Therefore, despite extensive research programs by biopharmaceutical companies and academia, there is a significant and unmet need for improved analgesic compounds, either based on novel or existing mechanisms. Furthermore, several cases of chronic pain eventually aggravate into neuropathic pain. Because of the large number of cases and the lack of targeted therapies, there has been considerable interest in the mechanisms that underpin neuropathic pain. One of the major surprises to have emerged over the last decades is that in experimental models of neuropathic pain, non- neuronal cells play a very active role in developing sensory abnormalities. In particular, multiple studies have demonstrated a critical role for Schwann cells and satellite glial cells (SGCs) in the PNS. However, to move these advancements towards their translational application, sufficient basic knowledge on neuropathic pain neuron-glia pathways, and tools for target and compounds discovery and validation, is still needed. In particular, it is not clear how exactly glial cells induce the hyper-excitable state in pain-signaling neurons. Moreover, pain mechanisms are not always controlled in the same way in preclinical species and humans. This work illustrates how the excitability of sensory neurons is strongly affected by the presence of glial cells. The absence of glial cells leads to an almost complete silencing of sensory neurons without affecting their survival. It has been proved that sensory neurons deprived of their glial cells can still generate action potentials. However, there is a delay in the onset of an action potential, as they require a higher stimulation to generate such action potential. It also shows that most glial cells in ganglia are represented by Schwann cells, leading to the hypothesis that these cells are essential for neuronal excitability in the PNS. It also demonstrates that these glial cells are not required to be in strict contact with DRG neurons to affect neuronal excitability but is sufficient for them to be in the same culture media. Furthermore, this work assesses a downregulation of specific genes in sensory neurons grown without glial cells, which correlates with the same genes being upregulated in established in vivo pain models. These findings support the hypothesis that glial cells play a crucial role in the excitability of sensory neurons. Therefore, they may be deeply involved in the generation of painful states, including those typical of neuropathic pain.

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