Hutton, EJ; (2017) The skin as a window on mechanisms of neuropathy and neuropathic pain. Doctoral thesis , UCL (University College London).

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Abstract

Neuropathies are common, yet the pathogenic mechanisms of many remain incompletely understood. Animal and cell models have provided much useful information about disease mechanisms, and yet translation of this knowledge to clinical practice and disease therapies is often disappointing. One of the difficulties in studying human nerves is limited availability of tissue, due to the morbidity of peripheral nerve (usually sural nerve) biopsy. I sought to evaluate the utility of cutaneous nerves, both generally as a tool to assess the relevance of pathogenic mechanisms identified in animal studies in human disease, and also specifically in evaluating whether immune changes in the skin may play a role in the development of neuropathic pain. Animal models have suggested that proinflammatory cytokines exert algesic effects on nerves, whilst anti-inflammatory cytokines have a counter-regulatory analgesic effect (Üçeyler et al., 2009). More recently, support for a link between variability in systemic and / or local cytokine balance and pain in neuropathy has begun to emerge (Üçeyler et al., 2007c, Üçeyler et al., 2010). Despite some support for a link between painful neuropathies and increased inflammatory and / or decreased antiinflammatory cytokines, it remains unclear whether the immune changes reflect underlying neuropathological processes, a response to nociceptor activation, variability in individual immune response to nerve damage or are a biomarker of another factor indirectly modulating both pain and immune function. It is also unclear whether immune-nerve interactions are unidirectional or bidirectional: does increased nociceptor firing modulate local immune function or does immune response to nerve damage modulate activity of remaining undamaged fibres, or is there a combination of these factors? I sought to understand the effect of acute nociceptor activation on skin immune profile, as well as whether changes in chronic neuropathy would be associated with the presence and intensity of pain

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