| Summary: | Pain is an intrinsic mechanism that promotes our survival by helping us to avoid injury. However, chronic pain remains a significant clinical burden and remains poorly treated. The development of new analgesic drugs may significantly improve quality of life for chronic pain patients. This thesis investigates the mechanisms of pain sensation and also suggests some novel analgesic drug targets by using molecular, genetic, and transgenic approaches. Firstly, a novel function of sodium channel Nav1.7 is explored. Microarray data showed that gene expression profiles are dramatically altered in dorsal root ganglia from Nav1.7 null mice. These changes were confirmed by real-time qRT-PCR. Altered expression of preproenkephalin (Penk) and carcinoembryonic antigen-related cell adhesion molecule 10 (Ceacam10) may contribute to the pain insensitive phenotype seen in Nav1.7 nulls. The gene expression changes were further explored using in vitro cell based assays, showing a potential role of sodium ions in controlling transcription of Penk. Secondly, we study a family with six members affected with a pain insensitive phenotype characterized by multiple painless bone fractures and frequent painless lesions caused by burning stimuli. A novel point mutation in ZFHX2, encoding a putative transcription factor expressed in small diameter sensory neurons, was identified. By analysing Zfhx2 knockout and BAC transgenic mice bearing the orthologous mutation, we confirm that ZFHX2 is crucial for normal pain perception. We study how the mutation disrupts ZFHX2 function, resulting in altered downstream expression of pain-related genes. Thirdly, a patient with small fibre neuropathy and erythromelalgia-like symptoms was genetically analysed. Using exome sequencing and detailed bioinformatics analyses, I have shortlisted three missense mutations in the genes CWC22, TMEM8B and ATL3 that are potentially pathogenic. By studying genes mutated in families with rare inherited pain disorders, this thesis broadens our understanding of pain sensation and highlights new routes to develop better analgesic drugs.
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