Exploring the role of CASPR2 in neuropathic pain
<p>Neuropathic pain is caused by a lesion or disease affecting the somatosensory nervous system affecting 7-10% of the general population. Neuropathic pain is characterised by pathophysiological changes within the nervous system that trigger disordered transmission of sensory signals. There is...
| Հիմնական հեղինակ: | |
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| Այլ հեղինակներ: | |
| Ձևաչափ: | Թեզիս |
| Լեզու: | English |
| Հրապարակվել է: |
2023
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| Խորագրեր: |
| Ամփոփում: | <p>Neuropathic pain is caused by a lesion or disease affecting the somatosensory nervous system affecting 7-10% of the general population. Neuropathic pain is characterised by pathophysiological changes within the nervous system that trigger disordered transmission of sensory signals. There is a critical need for targeted therapeutics for neuropathic pain, as current treatments are challenged by limited efficacy and poor tolerance. Understanding the induction and mechanism of neuropathic pain is crucial for the development of novel, efficacious therapies for its treatment.</p>
<p>Preclinical models of neuropathic pain illustrate that voltage-gated potassium channels (VGKCs) are essential in limiting neuronal excitability and disruption of these channels has been shown to contribute to neuropathic pain. Contactin-associated protein-like 2 (CASPR2) is a transmembrane protein part of the VGKC complex. CASPR2 is a known target of autoantibodies in patients with neuropathic pain, and CASPR2 autoantibodies have been shown to cause neuropathic pain by disrupting VGKC channel distribution in sensory neurons. This disruption caused increased neuron excitability and elicited pain-like behaviour in mice. Conversely, increased expression of CASPR2 in cultured peripheral sensory neurons led to reduced excitability- suggesting that modulation of CASPR2 expression could be a viable therapeutic approach for neuropathic pain.</p>
<p>This thesis endeavours to understand the effect of CASPR2 overexpression on pain sensibility and to elucidate the pathogenic mechanisms of patient CASPR2 autoantibodies. We investigate the effect of CASPR2 overexpression and explore its therapeutic potential using preclinical models. The overexpression of CASPR2 in nociceptors and sensory neurons of mice did not significantly alter mechanical or thermal pain sensitivity but reduced capsaicin-induced acute pain. This suggests that CASPR2 may modulate other proteins and regulate the excitability of specific neuronal populations. Future experiments are required to establish whether CASPR2 overexpression is sufficient to increase the surface expression of Kv1 channels or other proteins that may alter capsaicin sensitivity. The characterisation of the CASPR2 autoantibody-binding using cultured rodent neurons revealed differential binding of CASPR2 IgG from patients with and without neuropathic pain. Internalisation assays showed that CASPR2-IgG could internalise in sensory neurons in an antigen-specific manner. Taken together, these assays demonstrate the value of thorough patient IgG screening in strengthening clinical-serological correlations. Further elucidation of the pathogenic mechanisms of autoantibodies will likely promote the discovery and use of targeted therapies for neuropathic pain.</p> |
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