O2 Reduced Susceptibility to Migraine-Related Phenotypes in Familial Natural

Introduction There is a complex bidirectional relationship between sleep and migraine which is poorly understood. Anecdotal evidence suggests that some Familial Natural Short Sleepers (FNSS--who sleep on average 4–6 hours a night) may have reduced pain sensitivity. Therefore, we sought to determine whether there are altered migraine-related phenotypes in FNSS transgenic mice, and the role of potential metabolic pathways. Methods Male and female transgenic FNSS mice harbouring the P384R mutation in the hDEC2 gene, alongside C57BL/6J wild-type littermates, underwent validated translational measures of migraine-related phenotypes. This involved assessing mechanical, thermal, and light sensitivity using the von Frey assay under normal conditions, following sleep deprivation, and after exposure to the migraine trigger nitroglycerin. Metabolite concentrations in whole brains were analysed using nuclear magnetic resonance spectroscopy at baseline and following acute sleep deprivation. Results We found no significant differences in thermal (p = 0.731) or mechanical sensitivity (p = 0.572) in hDEC2-P384R mice compared to wild-type littermates at baseline. Both hDEC2-P38R (p = 0.018) and wild-type littermates (p = 0.007) exhibited orofacial mechanical allodynia in response to acute sleep deprivation. However, once exposed to the clinical migraine trigger nitroglycerin, hDEC2-P384R mice did not display orofacial mechanical sensitivity (p = 0.476) and photophobia (p = 0.174) when compared to wild-type littermates. hDEC2-P384R mice also exhibited a significant increase at baseline compared to wild-type littermates in metabolites underlying energy metabolism (ATP (p = 0.004); adenosine (p = 0.048)); and anti-oxidative stress (alanine (p = 0.048). Discussion These findings suggest that this FNSS allele may confer reduced sensitivity to specific migraine triggers. Consequently, our results provide insight into potential genetic and metabolic mechanisms that could reduce susceptibility to migraines, highlighting a possible link between sleep, metabolism, and headache pathophysiology.