Investigating the role of GWAS-identified NCX3 and Gas7 in pain

This thesis reports the results of a genome-wide association study (GWAS) of experimental pain in healthy volunteers and focuses on the validation of the identified genes as targets for pain research. We found a significant association between SLC8A3 encoding the sodium-calcium exchanger type-3 (NCX3) and wind-up ratio; as well as an association between Gas7 (growth arrest specific protein 7) and secondary punctate hyperalgesia after mustard oil. We were able to validate the role of both of these genes in pain processing through behavioural tests in mice lacking either NCX3 or Gas7. We found increased response to the second phase of the formalin test in mice with an NCX3 genetic deletion. Using in vitro calcium imaging and in vivo electrophysiology in the same mouse line, we observed increased intracellular calcium following stimulation, slowed calcium clearance and increased wind-up which could be evoked at lower frequencies. On the other hand, mice with a Gas7 genetic ablation showed decreased pain behaviour after capsaicin treatment. We also performed in vivo electrophysiology and dorsal horn dendritic spine analysis, searching for functional and structural mechanisms linked to our behavioural results. While this work is still on-going, our attempt to back-translate GWAS results, has revealed and validated two important and novel pain genes, one of which, NCX3, showed a distinct mechanism of action in the spinal dorsal horn