By studying healthy women who do not request analgesia during their first delivery we investigate genetic effects on labour pain. Such women have normal sensory and psychometric test results, except for significantly higher cuff-pressure pain. We find 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 KV2.1 inactivation because it fails to traffic to the plasma membrane. In vivo, Kcng4 (KV6.4) expression occurs in 40% of retrograde labelled mouse uterine sensory neurones, all of which express KV2.1, and over 90% express 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.
