Neurophysiological investigation of key nociceptor voltage-gated Na+ channels : temperature, age and disease-associated mutations

• Main Author: Mis, Malgorzata Anna
• Published: University of Bristol 2015
• Subjects: 616
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.690895

Pain is considered to be one of the most challenging and unmet medical needs. A considerable amount of research effort in both academia.and pharmaceutical industry has, and continues to be, aimed at elucidating the nociceptive and perceptual pain mechanisms in order to develop more effective treatments. Na+ channels are considered to be attractive and well validated analgesic targets. Recent human genetic studies have further implicated both tetrodotoxin (TTX)-sensitive and -resistant Na+ channel isoforms in the mechanisms of pain, arousing fresh interest in them as drug targets. In order to fully understand their role in various mechanisms underpinning nociception, it is essential to determine their contribution to the excitability of nociceptors under physiological as well as paineliciting conditions. This project aims to provide a detailed description of the role of previously validated TTX-sensitive and -resistant Na+ currents in the neurophysiology of mouse nociceptors at near-physiological temperature and different age points. The observed striking temperature and age dependence of Na+ current contribution to nociceptive neurophysiology is presented in chapters 3 and 4 respectively, and is expected to expand the current understanding of the role of Na+ channels in pain. While the current understanding of molecular nociception is based mainly on animal data, recent developments in the field of stem cells and genetics have the enormous potential to expand the knowledge of the mechanisms of human pain and nociception. Specifically, the potential use of human induced pluripotent stem cell-derived nociceptor-like neurons as a research tool in studying 'healthy' nociception, disease modelling and prediction of drug effectiveness has generated a lot of excitement and reinvigorated the concept of personalised medicine in pain research. The data presented in chapter 5 point to iPSe-derived nociceptor-like neurons as an effective avenue in studying the neurophysiology of 'healthy' nociceptors as well as elucidating the molecular mechanisms of pain conditions, in this case primary inherited erythromelalgia.