Human Labour Pain is Influenced by the Voltage-Gated Potassium Channel K v 6.4 Subunit

We sought genetic effects on labour pain by studying healthy women who did not request analgesia during their first delivery. Extensive sensory and psychometric testing were normal in these women, except for significantly higher cuff-pressure pain. We found an excess of heterozygotes carrying the rare allele of SNP rs140124801 in KCNG4. The rare variant Kv6.4-Met419 exerts a dominant negative effect and cannot modulate the voltage-dependence of K v 2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, we observed Kcng4 (K v 6.4) expression in 40% of retrograde labelled mouse uterine sensory neurones, all of which expressed Kv2.1 and over 90% expressed nociceptor genes Trpv1 and Scn10a. In neurones overexpressing Kv6.4-Met419, the voltage-dependence of inactivation for Kv2.1 is more depolarised compared to neurones overexpressing Kv6.4. Finally, Kv6.4-Met419 overexpressing neurones have a higher action potential threshold. We conclude that Kv6.4 can influence human labour pain by modulating the excitability of uterine nociceptors.