The mechanisms underlying sensory dysfunction in human pain channelopathies

Neuropathic pain is a major cause of disability affecting 6% of the population and current treatments are inadequate. Aberrant sensory neuronal excitability due to altered ion channel expression and function is fundamental in the development of neuropathic pain. It is increasingly recognised that inherited ion channel variants can have a major impact on sensory function in humans: In Mendelian pain disorders distinct ion channel mutations are associated with both insensitivity to pain and enhanced pain states. Ion channel variants may also modulate the risk and severity of common acquired neuropathic pain syndromes. These ‘pain channelopathies' are not only relevant to clinical diagnostics but also provide fundamental insight into the normal and pathological function of sensory neurons. The aim of this project is to better understand the mechanistic link between ion channel variants and clinical pain states. In this work programme the starting point will be detailed clinical and electrophysiological phenotyping of patients with inherited channelopathies. Novel cellular and animal models will be used to understand how ion channel variants result in aberrant excitability and altered sensory function. Validation of such models would then allow them to be used as a platform to screen analgesic treatments targeting these ion channels.